Breast Cancer: Recurrent Genomic Alterations

Table 1 - Clinically significant copy number alterations and regions of loss of heterozygosity in breast cancer. Table derived from Geiersbach et al., 2018 [PMID 32087595] with permission from Cancer Genetics.

Alteration	Relevant Gene(s)	CGC Evidence Level†	Subgroup Association(s)
1q gain	unknown	2	Most common copy number alteration, often with 16q loss; all subtypes
8p11.2 amplification	FGFR1, ZNF703	2	METABRIC IntClust6, ER positive
8q24 amplification	MYC	2	METABRIC IntClust9, ER positive
9p24 amplification	JAK2, CD274, PDCD1LG2	2	Enriched in TNBC
10q23.3 loss or LOH	PTEN	2	Enriched in TNBC and in lobular carcinoma
11q13-q14 gain / amplification	CCND1, EMS1, and others	2	METABRIC IntClust2
16q loss / LOH	CDH1	2	METABRIC IntClust2, ER positive
17p loss / LOH	TP53	2	TNBC, basal-like intrinsic subtype
17q12 amplification	ERBB2 (HER2)	1	METABRIC IntClust5, HER2-enriched
17q21 amplification	TOP2A	2	METABRIC IntClust5, HER2-enriched
17q23 amplification (“17q distal amplicon”)	RPS6KB, others	2	METABRIC IntClust1
19q12	CCNE1	2	METABRIC IntClust5; HER2-enriched
20q gain; 20q13 amp	AURKA, GNAS, ZNF217	2	METABRIC IntClust1, ER Positive

† See table below Table 2 for CGC Evidence levels

Abbreviations: TNBC, triple negative breast cancer; LOH, loss of heterozygosity.

Table 2 - Major clinically significant genes / gene regions associated with somatic or germline alterations in breast cancer.

Gene Symbol	Clinical Significance Level	Functional Mechanism	OMIM	COSMIC	cBioPortal	Types of Genomic Alterations	Comments	References (PMID)
ABL2	2	Gain of function	164690	ABL2	ABL2 breast	amplification, altered expression, sequence variants	Diseases: amplification of primarily ABL2 is seen across BC subtypes. Prognosis: poor prognostic marker in metastatic BC. ABL-targeted small molecule kinase inhibitors may be efficacious in cancers with ABL2 positive rearrangements (primarily ALL)	23842646; 32067942; 16740702
AKT1	1	Gain of function	164730	AKT1	AKT1 breast	sequence variants, amplification	Therapy: AKT inhibitors (FDA approved for E17K per CAPItello-291 trial); resistance to CDK4/6 inhibitors; Diseases: Metastatic BC, ER positive BC, lobular CA. Prognosis: risk of early relapse. Mutations occur early and are found in papillary lesions, proliferative lesions and cancer precusors. Absent in mucinous carcinoma (PMID: 22705004).	19418217; 19898424; 22705004; 23352210; 24186142; 26926684; 37256976; 38811720
ALK	2	Gain of function	105590	ALK	ALK breast	fusion	Therapy: ALK inhibitors. Very rare in breast cancer. More commonly associated with inflammatory myofibroblastic tumor (IMT), which can affect the breast. Can also be seen in ALK-positive histiocytosis in the breast.	32348852; 34423228; 34650924; 35171116; 34482333
APC	2	Loss of function	611731	APC	APC breast	sequence variants, epigenetic modification	Diseases: fibromatosis, TNBC. Therapy: mutations and hypermethylation associated with therapy resistance; Prognosis: APC mutation associated with poor prognosis in TNBC	11823972; 34370741; 26049416; 35936696; 33369461; 35523804
AR	2	Gain of function	313700	AR	AR breast metastatic	altered expression, sequence variants, amplification	Therapy: androgen receptor inhibitor therapy for luminal AR-positive TNBC. AR splice variants lacking the ligand binding domain can occur pre or post treatment and may lead to constitutive activation of AR signaling and resistance to AR inhibition. Diseases: AR is expressed in 70-90% of breast cancers overall. AR positive is associated with apocrine features in TNBC and luminal AR subtype.	34593966; 31822498; 36097802; 35986801; 29453314; 23245877
ARID1A	2	Loss of function	603024	ARID1A	ARID1A breast	sequence variants, other structural rearrangement	Diseases: endocrine-resistant ER+ BC. Enriched in special subtypes including neuroendocrine tumors, solid basaloid subtype of adenoid cystic carcinoma. Therapy: may be responsive to Ezh2 inhibitors; also may be responsive to Atr, PARP, and BET domain inhibitors	31932695; 33148628; 34804958; 26770240; 25686104; 27958275; 26069190; 29760405
ATM	1	Loss of function	607585	ATM	ATM breast	sequence variants, other structural rearrangement	Diseases: hereditary BC (moderate penetrance, 21-24% risk according to NCCN, c.7271T>G higher penetrance) but most mutations detected in tumors are somatic not germline; (odds ratio 2.10, 95% CI 1.71–2.57 in 2022 NEJM study). ER positive BC. Therapy: PARP inhibitor (preclinical use - limited/conflicting evidence); no contra-indications for radiotherapy at this time	33471991; 21787400; 16832357; 30504931; 39636577; 29506079
ATR	2	Loss of function	601215	ATR	ATR breast	sequence variants, other structural rearrangement	Diseases: TNBC. Therapy: Potentially targetable with PARP inhibitors and ATR inhibitors. ATR mutations can be germline or somatic. DNA damage response pathway gene.	38539474
AURKA	2	Gain of function	603072	AURKA	AURKA breast	amplification	Therapy: resistance to CDK4/6 inhibitors, assocaited with poor prognosis, in multiple clinical trials	29180466; 23186136; 36892847; 25362855; 20607239
AXIN2	2	Loss of function	604025	AXIN2	AXIN2 breast	sequence variants, other structural rearrangement	Diseases: Inactivating alterations in a subset of ILC with retained CDH1 gene expression	38347189; 39941785
BAP1	2	Loss of function	603089	BAP1	BAP1 breast	sequence variants, other structural rearrangement	Diseases: hereditary cancer but breast cancer not an established association. Therapy: PARP inhibitor (preclinical and some clinical trials) for association with HRD.	16341802; 32776290; 35905855; 33866194
BARD1	1	Loss of function	601593	BARD1	BARD1 breast	sequence variants	Diseases: ER-negative BC. Constitutional pathogenic variants (truncating) associated with hereditary BC (moderate penetrance), HRD. Slight increased risk of breast cancer (odds ratio, 2.09; 95% CI, 1.35 to 3.23 in NEJM 2022 study).	20301425; 33471991; 31142030; 30504931
BRAF	2	Gain of function	164757	BRAF	BRAF breast	sequence variants	Diseases: TNBC, adenoid cystic carcinoma; Therapy: BRAF, MEK inhibitors.	26095796; 27135926; 32206360; 34818649; 36531075
BRCA1	1	Loss of function	113705	BRCA1	BRCA1 breast	sequence variants, epigenetic modification, other structural rearrangement	Diseases: hereditary BC (high penetrance); TNBC; ovarian, other cancers. Associated with tandem duplicator phenotype, HRD. Therapy: PARP inhibitors, Prediction: reversion mutations in cfDNA resistant to PARP inhibitors.	20301425; 33471991; 28578601; 31421928; 28765325; 30110579
BRCA2	1	Loss of function	600185	BRCA2	BRCA2 breast	sequence variants, other structural rearrangement	Diseases: hereditary BC (high penetrance); ER positive BC; ovarian & other cancers, HRD. Therapy: PARP inhibitors; Prediction: reversion mutations in cfDNA resistant to PARP inhibitors.	20301425; 33471991; 28578601; 31421928; 28765325; 30110579
BRIP1	3	Loss of function	605882	BRIP1	BRIP1 breast	sequence variants	Diseases: refuted evidence for hereditary BC (but definitive evidence for ovarian cancer). HRD. Therapy: PARP inhibitor (preclinical use)	20301425; 29368626; 30062102; 30504931; 33471991
C19MC	3	Gain of function	NA	NA	NA	altered expression	Diseases: Basal-like TNBC shows elevated C19MC miRNA expression. C19MC is not a gene but a gene cluster that encodes 46 micro RNAs (miRNAs) at ‘q’ arm of chromosome 19, band chr19q13.42 within a span of ~100kb. The miRNAs interact with CEBPB to drive gene expression.	18193036; 19339516; 30335837; 37840066
CBFB	3	Other/Complex	121360	CBFB	CBFB breast	sequence variants, amplification, other structural rearrangement	Diseases: ER positive BC, metastatic BC. Prognosis: uncertain; associated with improved survival but cooperates with PIK3A to promote tumor progression	22722202; 32711101; 31061501; 36799863
CCN6	2	Loss of function	603400	CCN6	CCN6 breast	sequence variants, other structural rearrangement	Diseases: metaplastic BC, basal- like or claudin low TNBC	18593979; 32265444; 30220054; 34940056; 27086280
CCND1	2	Gain of function	168461	CCND1	CCND1 breast	amplification	Diseases: ER positive BC, luminal B subtype; Therapy: CDK4/6 inhibitor in ER-positive HER2-negative BC w/ CCND1 amplification; Prognosis: amplification associated with poor long term prognosis.	31231556; 30819233; 25524798; 32885893; 35784572
CCND3	3	Gain of function	123834	CCND3	CCND3 breast	amplification, sequence variants	Diseases: all subtypes; one study (25927147) indicates higher frequency in metaplastic BC	25927147; 27161491
CCNE1	2	Gain of function	123837	CCNE1	CCNE1 breast	amplification, altered expression, sequence variants	Disease: metastatic BC; overexpression associated with poor prognosis; Therapy: resistance to CDK4/6 inhibitors. Additionally, CCNE1 amplification or activating mutations may be sensitive to inhibitors of Cdk2, the protein that Cyclin E1 binds and activates. Other potential therapies include combined Cdk and Akt or PI3K inhibitors, and Wee1 inhibitors.	40243688;30807234; 30665374; 32885893; 35005994; 23185313
CD274	1	Gain of function	605402	CD274	CD274 breast	altered expression, amplification	Encodes PD-L1. Diseases: metastatic TNBC; associated with TILs; Prognosis: elevated PD-L1 expression favorable. Treatment: PD-L1 expression predicts sensitivity to PD-L1 blockade; 2 FDA approved IHC assays for mTNBC - Roche VENTANA (SP142) for Tecentriq (atezolizumab) and Agilent (22C3) pharmDx assay for KEYTRUDA (pembrolizumab). Amplification currently of uncertain significance.	26317899; 26541326; 27390646; 25897014; 33314633
CDH1	1	Loss of function	192090	CDH1	CDH1 breast	sequence variants, other structural rearrangement, altered expression	Diseases: invasive lobular carcinoma, luminal A molecular subtype; constitutional variants associated with hereditary breast & gastric cancer (high penetrance) (OMIM * 192090). However, most CDH1 loss of function mutations detected in ILC are somatic not germline (0.3% germline in one study 31263054).	20301425; 33471991; 26451490; 35277969; 16061854; 30504931; 31263054
CDK12	2	Loss of function	615514	CDK12	CDK12 breast	sequence variants	Diseases: TNBC, adenoid cystic carcinoma; Therapy: CDK12/CDK13 inhibitors induce BRCAness phenotype (preclinical) via synthetic lethality in combination with PARP inhibitors	31857685; 31668947; 30104286; 25561469; 33295810
CDK13	2	Loss of function	603309	CDK13	CDK13 breast	sequence variants	Diseases: TNBC, adenoid cystic carcinoma; Therapy: CDK12/CDK13 inhibitors induce BRCAness phenotype (preclinical)	31668947; 25561469; 33295810
CDK4	2	Gain of function	123829	CDK4	CDK4 breast	amplification, sequence variants	Therapy: CDK4/6 inhibitors to ER-positive HER2-negative BC in pre-menopausal women	31101994; 9916925; 35712501; 31632494; 32145796
CDK6	2	Gain of function	603368	CDK6	CDK6 breast	amplification, sequence variants, other structural rearrangement	Therapy: CDK4/6 inhibitors to ER-positive HER2-negative BC in pre-menopausal women; amp can be resistance mechanism to CDK4/6 therapy	31101994; 35712501; 27748766; 32145796; 29180466; 40551183
CDKN1B	2	Loss of function	600778	CDKN1B	CDKN1B breast	sequence variants, other structural rearrangement	Disease associations: ER positive (luminal) BC. Prognosis: mutations associated with tumor aggressiveness. Germline mutations breast, prostate, and small intestinal neuroendocrine tumors	30065701; 33140857
CDKN2A	2	Loss of function	600160	CDKN2A	CDKN2A breast	sequence variants, other structural rearrangement, epigenetic modification	Disease associations: metastatic BC. Treatment: CDK4/6 inhibitor in ER-positive HER2-negative BC w/ loss of CDKN2A. Prognosis: mutation associated with poor outcome	28027327; 25524798; 36052076
CHD4	3	Gain of function	603277	CHD4	CHD4 breast	sequence variants	Disease associations: ER positive (luminal) BC. Poor prognostic indicator.	32699137; 33981601; 27779108
CHEK2	1	Loss of function	604373	CHEK2	CHEK2 breast	sequence variants	Disease associations: constitutional pathogenic variants associated with hereditary BC (moderate penetrance); especially ER positive BC. Loss of remaining CHEK2 allele is associated with chromosomal instability but not HRD. c.1100delC germline a/w 2-3x increased risk for BC in women and 10x increased risk in men. (odds ratio, 2.13; 95% CI, 1.60 to 2.84 in 2022 NEJM study)	20301425; 33471991; 35020107; 35135604; 30504931
CREBBP	2	Loss of function	600140	CREBBP	CREBBP breast	sequence variants, amplification	Diseases: all subtypes, especially associated with adenoid cystic carcinoma and neuroendocrine tumors. CREBBP is a gene in the chromatin modification / remodeling pathway.	31857685; 37660928; 33827682
CTCF	3	Loss of function	604167	CTCF	CTCF breast	sequence variants, altered expression	Disease associations: ER positive BC, enriched in metastatic breast cancer. Associated with aberrant DNA methylation patterns. Therapy: hormone resistance.	30205045; 24794443; 32374727
CTLA4	2	Other/Complex	123890	CTLA4	CTLA4 breast	altered expression	Diseases: BC, positive correlation with immune cell infiltration. Therapy: Overexpression targetable with anti-CTLA4 antibody therapy. Prognosis: favorable with overexpression.	32434947; 38725802
CTNNA1	2	Loss of function	116805	CTNNA1	CTNNA1 breast	sequence variants	Disease associations: Inactivating mutations (somatic or germline) in a subset of ILC. Germline pathogenic variants associated with hereditary diffuse gastric and lobular breast cancer syndrome; constitutional CTNNA1 variants are found in a minority of patients with familial ILC negative for CDH1 variants.	23208944; 29774524; 32758476; 36741258; 34425242
CTNNB1	2	Gain of function	116806	CTNNB1	CTNNB1 breast	sequence variants, altered expression	Diseases: ILC, TNBC including acinic cell carcinoma, metaplastic carcinoma (absent or aberrant beta catenin expression); desmoid-type fibromatosis of the breast. Targeted anti-WNT signaling therapies being investigated in clinical trials.	26011570; 32590455; 18593979; 34456337; 39941785
CTNND1	2	Loss of function	601045	CTNND1	CTNND1 breast	altered expression, other structural rearrangement	Diseases: Inactivating alterations / aberrant expression in a subset of ILC with retained CDH1 gene expression. Diffuse cytoplasmic staining of CTNND1 (p120) by IHC, instead of expected membranous staining, is another marker of ILC.	37443169; 38347189; 39941785
CTTN	2	Gain of function	164765	CTTN	CTTN breast	amplification, altered expression, sequence variants	Diseases: primary breast cancer. Amplified in one four core regions within 11q13 that can be amplified independently or together in different combinations (11q13 amp in about 15% of breast cancers).	10706127; 20213079; 12755491; 1532244; 16652145
CYP19A1	2	Gain of function	107910	CYP19A1	CYP19A1 breast	amplification, altered expression	Therapy implications: CYP19A1 (encoding aromatase) gene amplification increases aromatase activity and leads to resistance to endocrine therapy. Diseases: ER positive BC, metastatic	28112739; 32943456; 34133482
EGFR	2	Gain of function	131550	EGFR	EGFR breast	amplification, sequence variants, other structural rearrangement	Diseases: metaplastic BC, basal- like or claudin low TNBC. Therapy: EGFR amplification (pre-existing or de novo) associates with resistance to hormone therapy.	15920544; 25927147; 7606735; 35507014; 30205045
EP300	2	Other/Complex	609773	EP300	EP300 breast	sequence variants, other structural rearrangement, altered expression	Diseases: TNBC, adenoid cystic carcinoma, metaplastic BC; Therapy: possible implications for aldo-keto reductase inhibitor. Ep300 is a a histone acetyltransferase and functions as transcriptional activator of CDH1.	30862505; 10700188; 27491809; 30132219; 36782375;
ERBB2	1	Gain of function	164870	ERBB2	ERBB2 breast	amplification, altered expression, sequence variants	Also known as HER2. Diseases: Amplification in 15% of BC. Sequence variants associated with apocrine and pleomorphic lobular features. Therapy: anti-HER2 mAb (trastuzumab and pertuzumab) for classical overexpression/amplification per ASCO/CAP guidelines, and antibody-drug conjugate (ADC) therapy for HER2-low and ultralow expression per DESTINY-04 and -06 and DAISY trials; HER2 mutations associated with resistance to CDK4/6 inhibitors and resistance to hormone therapy	3798106; 9256133; 11248153; 29846122; 35665782; 37488289; 39282896
ERBB3	2	Gain of function	190151	ERBB3	ERBB3 breast	sequence variants, amplification	Diseases: lobular BC, TNBC case report indicated exceptional response to trastuzumab (PMID: 34250408)	26926684; 34250408
ERBB4	2	Other/Complex	600543	ERBB4	ERBB4 breast	sequence variants, altered expression	Diseases: ER positive, HER2 negative BC (typically ERBB4 overexpression), enriched in acinic cell carcinoma. ERBB4 activating mutations may be sensitive to ErbB family inhibitor afatinib. Complex mechanisms with either gain or loss of function being oncogenic; thus, targeted therapy must be informed by mechanism of mutation.	22888144; 24791013; 20943952; 34885957; 27713419
ESR1	1	Gain of function	133430	ESR1	ESR1 breast metastatic	sequence variants, amplification, fusion, altered expression	Therapy: Hotspot mutations in ligand binding domain (LBD) occur in patients with prior AI therapy, conferring resistance to aromatase inhibitors, SERMs (e.g. tamoxifen). May be responsive to SERDs (e.g. fulvestrant; elacestrant, imlunestrant, vepdegestrant). Specific point mutations associated with differential response to fulvestrant. Tyr537Ser and Asp538Gly mutants involve hydrogen bonding of the mutant amino acids with Asp351, thus favoring the agonist conformation of the receptor (ligand independent signaling). N-terminal ESR1 fusions lack an intact LBD. Fusions often co-ccur with sequence alterations (polyclonality). Diseases: ER positive BC, metastatic BC with prior endocrine therapy. Diagnosis: Nuclear expression of ER is a key biomarker for HR positive primary breast cancer. Prognosis: mutations, amplification, and fusions associated with decreased overall survival.	24185510; 24185512; 27986707; 28027327; 29360925; 35584336; 36125660; 36198774; 39660834
ETV6	1	Gain of function	600618	ETV6	ETV6 breast	fusion, other structural rearrangement	Diseases: Secretory carcinoma. Prognosis: favorable (clinically indolent). Low mutation burden, simple genomes. structural rearrangement (fusion) with NTRK3 in secretory carcinoma. BCL2L14–ETV6 (cryptic adjacent gene rearrangement) in 4.4%-12.2% TNBC ass'ed with more aggressive histologic features like necrosis and high tumor grade. BCL2L14–ETV6 in TNBC associated with more aggreessive behaviour	12450792; 15101049; 28548128; 32321829
FAT1	2	Loss of function	600976	FAT1	FAT1 breast	sequence variants, other structural rearrangement, altered expression	Diseases: metaplastic BC, basal- like or claudin low TNBC; Resistance to CDK4/6 inhibitors. Blacks more likely to have compared to whites	32265444; 30537512; 28153863; 29180466; 33021035; 39879109
FBXO4	2	Loss of function	609090	FBXO4	FBXO4 breast	sequence variants, altered expression	Recurrent mutations in phyllodes tumors, low expression associated with poor prognosis	21030860; 35565262; 29137327; 30341246
FBXW7	2	Loss of function	606278	FBXW7	FBXW7 breast	epigenetic modification, other structural rearrangement, sequence variants	Therapy: chemoresistance (emerging evidence). Diseases: TNBC, adenoid cystic carcinoma (rare sequence variants). Mutations often heterozygous. Mutated in Microglandular adenosis (MGA) with or without associated TNBC, low expression associated with poor prognosis, new population studies	21122106; 26095796; 27135926; 27409838; 30791487; 33382535; 33070870; 38268032; 37902422; 39445291; 39277826
FGFR1	1	Gain of function	136350	FGFR1	FGFR1 breast	fusion, amplification, sequence variants, altered expression	Diseases: mucinous BC, invasive micropapillary carcinoma, ER-positive luminal B; Therapy: resistance to endocrine therapy; potential sensitivity to FGFR1 inhibitors. Loss is associated with independent poor prognosis in TNBC-preganancy associated carcinomas	26762307; 20179196; 32723837; 33579347; 35804935; 34522456; 37541273; 37980453
FGFR2	1	Gain of function	176943	FGFR2	FGFR2 breast	fusion, amplification, sequence variants	ER+ metastatic tumors resistant to ER-targeted theapies, resistance to CDK4/6 inhibitors, resistance to HER2 targeted therapies	32723837; 35005994; 37541273; 37980453
FGFR3	1	Gain of function	134934	FGFR3	FGFR3 breast	fusion, altered expression, amplification, sequence variants	ER+ metastatic BC resistant to endocrine therapy	32723837; 35653148; 34522456; 37541273; 37980453
FGFR4	1	Gain of function	134935	FGFR4	FGFR4 breast	fusion, altered expression, amplification, sequence variants	ER+ metastatic tumors resistant to ER-targeted theapies. Amplification mostly seen in HER2 subtype	32723837; 34522456; 34344433; 37541273; 37980453
FLNA	2	Loss of function	300017	FLNA	FLNA breast	sequence variants, other structural rearrangement	Diseases: phyllodes tumor	26437033; 30511242; 35691725
FOLR1	3	Gain of function	136430	FOLR1	FOLR1 breast	altered expression	Diseases: ER/PR-negative and triple-negative breast cancers; overexpression associated with higher grade tumors and poor prognosis. Therapy: clinically approved targeted therapy is available for ovarian cancer. Clinical trials ongoing for breast cancer.	25928305; 24028341; 23961352; 35094917; 37244363
FOXA1	2	Gain of function	602294	FOXA1	FOXA1 breast	sequence variants, amplification	Diseases: ER positive BC, Enriched in special subtypes including neuroendocrine tumors, lobular BC. Therapy: associated with endocrine therapy resistance. Expression is associated with Less favorable outcome in non-luminal tumors (unlike in luminal tumors) namely in molecular apocrine tumors that are AR+	30205045; 26451490; 30205045
GATA3	2	Other/Complex	131320	GATA3	GATA3 breast	sequence variants	Diseases: ER positive BC; luminal; endocrine resistant mBC. Frameshift mutations predominate; most mutations impact exons 5 or 6 and impact the second ZF domain or carboxy terminus.Mutations in GATA3 in ctDNA in metastatic cancer is associated with changes in MDM2 pathways and potential vulnerability to MDM2 inhibition.	23000897; 29535312; 35653148; 34225008; 40439821
GNAS	3	Gain of function	139320	GNAS	GNAS breast	sequence variants, amplification	Disease: Fibrous Dysplasia (hereditary GNAS mut), familial male breast cancers [overexpression results in elevated proliferation and migration]. Mutation in Adenomyoepithelioma, low grade metaplastic carcinoma (fibromatosis like MC and low-grade adenosqumous carcinoma) , Juvenile papillomatosis, mucinous cytadenocarcinoma	28856726; 25490678; 25757876; 32355271; 32127014; 32088208; 40221995
GPS2	3	Loss of function	601935	GPS2	GPS2 breast	sequence variants, other structural rearrangement	Diseases: ER positive (luminal) BC.	33490071; 19858209
HGF	2	Gain of function	142409	HGF	HGF breast	amplification, altered expression, sequence variants	Diseases: TNBC basal-like subtype. Therapy: activating mutations confer sensitivity to HGF or MET inhibition and are associated with resistance to EGFR family tyrosine kinase inhibitors including trastuzumab. Prognosis: HGF activation is a poor prognostic indicator.	22850551; 25992381; 34344422
HRAS	2	Gain of function	190020	HRAS	HRAS breast	amplification, sequence variants	Diseases: postradiation angiosarcoma; metaplastic carcinoma; Q61 hotspot mutation in adenomyoepithelioma (ER-negative), may be targatable (MEK inhibitors)	31646390; 29946183; 34496925; 32355271
IDH2	1	Gain of function	147650	IDH2	IDH2 breast	sequence variants	Diseases: Tall cell carcinoma with reverse polarity / solid papillary carcinoma with reverse polarity. Mutations identified in breast cancers from Arabic descent. Wild type (wt) IDH2 maybe potentially targetable in TNBC.	27913435; 29785016; 29603332; 30227763; 31896809; 32322420; 34327780; 38658533
JAK2	2	Gain of function	147796	JAK2	JAK2 breast	sequence variants, amplification	Diseases: enriched in TNBC; Therapy: potential sensitivity to JAK2 inhibitors or Immune checkpoint inhibitors	26317899; 29933930; 30576871; 29761158; 30576871; 34626199
KDM6A	3	Loss of function	300128	KDM6A	KDM6A breast	sequence variants, other structural rearrangement	Diseases: Enriched in solid basaloid subtype of adenoid cystic carcinoma and metaplastic BC. KDM6A and KDM6B are H3K27me3-demethylases involved in post-translational modifications of histones; context-dependent modulation of tumor cell transition between epithelial and mesenchymal states. Mostly a role for loss of function but the mechanism is complex.	25927147; 29029452; 37660928; 34599282
KDR	2	Other/Complex	191306	KDR	KDR breast	sequence variants, amplification	Diseases: postradiation and primary angiosarcoma. In primary angiosarcoma , indicator of worse prognosis. Formerly named VEGFR2.	19723655; 31636652; 36376999; 32042194; 32123305
KMT2B	3	Loss of function	606834	KMT2B	KMT2B breast	sequence variants, other structural rearrangement, altered expression	Diseases: all subtypes; enriched in metaplastic BC (referred to as MLL2 gene).	25927147; 34544752; 35058979
KMT2C	2	Loss of function	606833	KMT2C	KMT2C breast	sequence variants, fusion	Diseases: enriched in special subtypes including solid basaloid subtype of adenoid cystic carcinoma, metaplastic BC, basal- like or claudin low TNBC, mucinous carcinoma; metastatic breast cancers, neuroendocrine neoplasms	28153863; 30649385; 31118521; 30649385; 34728787; 34599282; 33148628
KMT2D	2	Loss of function	602113	KMT2D	KMT2D breast	sequence variants	Diseases: enriched in solid basaloid subtype of adenoid cystic carcinoma, phyllodes tumor; metaplastic BC. NOTCH activation downregulates p63. Germline: Kabuki syndrome	26437033; 28153863; 28336670; 33782741; 34336928; 32383785; 30990809; 37660928
KRAS	3	Gain of function	190070	KRAS	KRAS breast	amplification, sequence variants	Diseases: metaplastic BC, apocrine, basal- like or claudin low TNBC. Rare.	28027454; 28153863; 29946183; 36358741; 36358725
LRP1B	3	Other/Complex	608766	LRP1B	LRP1B breast	sequence variants, amplification, other structural rearrangement	Observed in ~4.3% of breast cancers (CBioPortal), Nuclear LRP1B is assoc w/ poor patient prognosis, but patients with mutation LRP1B have favorable outcomes to immune checkpoint inhibitors in multiple cancers	30607440; 31164891; 33653800; 32850302
MAF	3	Gain of function	177075	MAF	MAF breast	amplification	Diseases: associated with bone metastases from larger, high-grade breast cancers. Bisphosphonates (Zoledronic acid) possible clinical use therapeutic, per AZURE and NSABP-B34 clinical trials.	26376684; 34377934; 29037984
MAML2	1	Gain of function	607537	MAML2	MAML2 breast	fusion	Diseases: mucoepidermoid carcinoma of the breast	19200580; 30380176; 32362174; 32550265
MAP2K4	3	Loss of function	601335	MAP2K4	MAP2K4 breast	sequence variants, other structural rearrangement	Preclinical study suggests sensitivity to MEK and ERK inhibitors	29795445; 31932411
MAP3K1	3	Loss of function	600982	MAP3K1	MAP3K1 breast	sequence variants, other structural rearrangement	Mutations associated with luminal A subtype BC; potential sensitivity to MEK inhibitors	31552290; 29795445
MDM2	2	Gain of function	164785	MDM2	MDM2 breast	amplification	Diagnosis: amplified in 5% (cBioPortal) to 13% (PMID:30237864) breast cancers; TP53 inactivator. Therapies: resistance to chemotherapy and radiotherapy; MDM2 inhibitors in development	30237864; 31440117; 30551517
MDM4	2	Gain of function	602704	MDM4	MDM4 breast	amplification	Diseases: Inflammatory BC, potential therapeutic target	33007869
MED12	2	Gain of function	300188	MED12	MED12 breast	sequence variants	Diseases: fibroadenoma, juvenile fibroadenoma, phyllodes tumor	26437033; 26860948; 29043292; 29315289; 28688536; 31662438; 33376197; 25865354; 34505197
MIB1	2	Other/Complex	608677	MIB1	MIB1 breast	altered expression	Diagnosis: Ki67 (MIB1 protein product) expression usually performed with ER, PR, and HER2 on a diagnostic biopsy. Therapy: Ki-67 >10% at 2 weeks after initiating endocrine therapy suggests a possible need for additional chemotherapy (POETIC trial). Prognosis: Ki-67 >10% correlates with poorer survival. Magee Equations can be used as a surrogate for Oncotype Dx to predict recurrence (https://path.upmc.edu/onlineTools/mageeequations.html).	33152284; 36096872; 36165933
MSH6	2	Loss of function	600678	MSH6	MSH6 breast	sequence variants, altered expression	Hereditary: Slightly increased risk of breast cancer (odds ratio, 1.96; 95% CI, 1.15 to 3.33 in 2022 NEJM study)	33471991
MTOR	2	Gain of function	601231	MTOR	MTOR breast	sequence variants	Diseases: TNBC, acinic cell carcinoma, [adenoid cystic carcinoma??]	26011570; 29417298; 31408724; 20190810; 28400999;
MYB	1	Gain of function	189990	MYB	MYB breast	fusion, other structural rearrangement, amplification	Diseases: Adenoid cystic carcinoma (MYB::NFIB is most common fusion)	19841262; 26095796; 29149504
MYBL1	1	Gain of function	159405	MYBL1	MYBL1 breast	fusion, other structural rearrangement	Diseases: TNBC, adenoid cystic carcinoma	29149504; 34599282; 29410490
MYC	2	Gain of function	190080	MYC	MYC breast	amplification, altered expression	Diseases: ER positive BC, TNBC, invasive micropapillary carcinoma, postradiation angiosarcoma. Prognostic: Amp is associated with higher grade, increased risk of relapse and mortality; Therapy: hormone resistance; resistance to CDK4/6 inhibitors	22113465; 29180466; 31243099; 30205045; 35005994
NCOR1	2	Loss of function	600849	NCOR1	NCOR1 breast	sequence variants, other structural rearrangement	Diseases: ER positive (luminal) BC; metastatic breast cancers	31118521; 22722201; 26451490; 30305115; 32811538
NECTIN4	2	Gain of function	609607	NECTIN4	NECTIN4 breast	amplification, altered expression	Therapy: potential marker for off label use of antibody drug conjugate therapy (EV). NECTIN4 encodes a cell adhesion molecule expressed in >50% invasive ductal carcinoma.	38059449
NF1	2	Other/Complex	613113	NF1	NF1 breast	sequence variants, other structural rearrangement, amplification	Therapy: endocrine resistance. LoF mutations may be targetable with inhibitors of MAPK pathway components, including MEK inhibitors. Diseases: Metastatic BC. hereditary syndrome with risk for breast & other cancers; risk is primarily associated with missense and nonsense mutations rather than whole gene deletions, suggesting a gain of function mechanism. Risk is modest (odds ratio, 1.76; 95% CI, 0.96 to 3.21 in 2022 NEJM study)	33471991; 31591187; 31118521; 30423024; 28637487; 30530636
NFIB	1	Gain of function	600728	NFIB	NFIB breast	fusion, rearrangement	Diseases: adenoid cystic carcinoma MYB partner in MYB-NFIB fusion, triple negative BC	30350349; 22015727; 19841262; 25217885; 29149504
NOTCH1	2	Gain of function	190198	NOTCH1	NOTCH1 breast	sequence variants, amplification	Diseases: enriched in TNBC, solid basaloid subtype of adenoid cystic carcinoma. Therapy: inactivating mutations potentially targetable with LGK974, a porcupine inhibitor currently in clinical trials. NOTCH activation downregulates p63. Reduced Notch1 expression associates with increased paclitaxel sensitivity.	40025676; 37660928; 34599282; 31857685; 26121683; 33384996; 24451948; 24277854; 22101766; 16166334
NOTCH2	2	Gain of function	600275	NOTCH2	NOTCH2 breast	sequence variants, amplification	Diseases: enriched in TNBC, solid basaloid subtype of adenoid cystic carcinoma. NOTCH activation downregulates p63.	31857685
NOTCH3	2	Gain of function	600276	NOTCH3	NOTCH3 breast	sequence variants, amplification	Diseases: enriched in TNBC, solid basaloid subtype of adenoid cystic carcinoma. NOTCH activation downregulates p63.	31857685; 33384996; 29795369; 28108512; 30180881
NOTCH4	2	Gain of function	164951	NOTCH4	NOTCH4 breast	sequence variants, amplification	Diseases: Diseases: enriched in TNBC, solid basaloid subtype of adenoid cystic carcinoma.	31857685; 33384996; 32104513; 34284787; 20068161
NPM1	3	Gain of function	164040	NPM1	NPM1	amplification, expression	occurs in ~1% of breast invasive carcinoma, primarily TNBC, mechanism = upregulation of NPM1 expression; poor prognosis, drug resistance in vitro	32245950; 30613163
NRAS	3	Gain of function	164790	NRAS	NRAS breast	amplification, sequence variants	Diseases: metaplastic BC, basal- like or claudin low TNBC	29946183; 24882719; 27628192; 24318467
NRG1	1	Gain of function	142445	NRG1	NRG1 breast	fusion	Therapy: Targetable alteration (FDA-approved therapy for NSCLC and pancreatic cancer). NRG1 encodes multiple isoforms of Nrg1, known as Neuregulin 1 or heregulin, that function as activating ligands for the ErbB3 and ErbB4 receptor tyrosine kinases, causing ERBB3 heterodimerization and downstream signaling of MAPK, PI3K pathways. In addition, NRG1 can function as a tumor suppressor (pro-apoptotic) and some structural rearrangements are inactivating (PMID: 33413557).	29610121; 33413557; 32916265; 39908431
NSD1	3	Loss of function	606681	NSD1	NSD1 breast	sequence variants	occurs in ~1% of breast cancer; essential for anti-estrogen sensitivity to breast cancer; silencing of NSD1 causes resistance to tamoxifen	21482774; 25611383; 34905470
NTRK1	1	Gain of function	191315	NTRK1	NTRK1 breast	amplification, sequence variants, fusion	Therapy: TRK inhibitors for fusions (including pan-Trk inhibitors larotrectinib, entrectinib, and repotrectinib); kinase domain mutations confer resistance to certain TRK inhibitors	29466156; 32348852; 28183697; 30093503; 31838007
NTRK2	1	Gain of function	600456	NTRK2	NTRK2 breast	amplification, sequence variants, fusion	Therapy: TRK inhibitors for fusions (including pan-Trk inhibitors larotrectinib, entrectinib, and repotrectinib); kinase domain mutations confer resistance to certain TRK inhibitors	29466156; 28183697; 31838007
NTRK3	1	Gain of function	191316	NTRK3	NTRK3 breast	fusion, amplification, sequence variants	Therapy: TRK inhibitors for fusions (including pan-Trk inhibitors larotrectinib, entrectinib, and repotrectinib); kinase domain mutations confer resistance to certain TRK inhibitors	12450792; 29466156; 28183697; 30093503; 31838007
NUP93	3	Gain of function	614351	NUP93	NUP93 breast	amplification, sequence variants, altered expression	Diseases: TNBC, claudin-low subtype, alterations are rare. Prognosis: in vitro evidence for association with disease progression in TNBC	27071718; 31959624
PALB2	1	Loss of function	610355	PALB2	PALB2 breast	sequence variants, other structural rearrangement	Diseases: hereditary BC (high penetrance), ovarian cancer risk. HRD.	22241545; 24485656; 28319063; 16793542; 30504931; 33247475; 33471991
PBRM1	2	Loss of function	606083	PBRM1	PBRM1 breast	sequence variants, other structural rearrangement	occurs in ~1-2% of metastatic breast cancer; synthetic lethality with PARP inhibitors, sensitizing for immunotherapy	33314633; 33888468; 33004031; 28977912; 26464681
PDCD1LG2	2	Gain of function	605723	PDCD1LG2	PDCD1LG2 breast	amplification	Diseases: enriched in TNBC; Therapy: potential sensitivity to Immune checkpoint inhibitors. PD-L2 (CD273) is the gene product. (part of 9p24.1 amp)	26317899; 26541326; 30576871; 34347720
PDGFRA	3	Gain of function	173490	PDGFRA	PDGFRA breast	sequence variants, amplification, other structural rearrangement, fusion	~1-2% breast carcinoma, associated with mesenchymal type TNBC, emerging therapeutic target, associated with aggressive disease	29380207; 23752188; 32152520; 34440080
PDGFRB	3	Gain of function	173410	PDGFRB	PDGFRB breast	amplification, sequence variants	inhibition of tumorigeneisis in BRCA1 deficienct BC cells in preclinical model	27161491; 22522925; 29380207
PGR	2	Gain of function	607311	PGR	PGR breast	sequence variants, altered expression	Diseases: expressed in HR positive breast cancer. Sequence alterations in ligand binding domain (most commonly Y890C) are implicated in hormone resistance (post hormone therapy treatment)	34057651; 34013318; 31942683; 28532429
PIK3CA	1	Gain of function	171834	PIK3CA	PIK3CA breast	sequence variants	Therapy: FDA approved (PI3K inhibitor alpelisib & AKT inhibitor capivasertib); acquired hormone resistance. Diseases: ER-positive BC, including micropapillary, proliferative lesions and invasive cancer precursors. Also in radial scars, codon 1047 most common, 64% overall. Absent in mucinous carcinoma (PMID: 22705004).	19418217; 19898424; 23352210; 24186142; 24193002; 30305115; 31091374; 32404150; 35653148; 40454641
PIK3R1	2	Loss of function	171833	PIK3R1	PIK3R1 breast	sequence variants	Diseases: metaplastic BC, basal- like or claudin low TNBC. Loss of function increases PI3K signaling and activates Akt. PI3K/Akt/mTOR inhibitors may be effective (clinical trials ongoing).	29636477; 31209687; 30181556; 34093841; 20212113; 23215720
PLCG1	3	Gain of function	172420	PLCG1	PLCG1 breast	sequence variants, amplification, altered expression	Diseases: sequence alterations recurrent in postradiation angiosarcoma (recurrent p.Arg707Gln mutation). Prognosis: Overexpression predictive of metastases in Luminal A, B breast cancer.	24633157; 31362705
PRKD1	2	Gain of function	605435	PRKD1	PRKD1 breast	sequence variants	Diseases: TNBC, adenoid cystic carcinoma, ER positive BC. Prognosis: increased gene expression associated with reduced disease free survival (especially in TNBC). Therapy: emerging target (siRNA, miRNA).	26895471; 29796183; 31676574
PTEN	1	Loss of function	601728	PTEN	PTEN breast	sequence variants, other structural rearrangement, epigenetic modification	Therapy: AKT inhibitor therapy capivasertib, resistance to trastuzumab (HER2 targeted therapy), increased sensitivity to AKT and mTOR inhibitors; Diseases: hereditary syndromic risk for breast and other cancers (high penetrance); lobular BC, TNBC. Majority (>99%) PTEN mutations detected in tumors are somatic not germline. Prognosis: higher risk of recurrence.	33471991; 29902286; 15324695; 32864625; 37256976; 30504931
PTPRB	3	Gain of function	176882	PTPRB	PTPRB breast	sequence variants	Diseases: postradiation angiosarcoma; Function: angiogenesis	24633157;
PTPRD	2	Loss of function	601598	PTPRD	PTPRD breast	sequence variants, other structural rearrangement, epigenetic modification	Tumor suppressor gene loss of function alterations in 4% breast cancer	18507500; 19478061; 22722201
RAD50	3	Loss of function	604040	RAD50	RAD50 breast	sequence alteration, other structural rearrangement	Diseases: limited evidence for hereditary BC (how often sporadic?)	30504931; 34782604
RAD51C	2	Loss of function	602774	RAD51C	RAD51C breast	sequence variants	Diseases: Slight increased risk for hereditary BC, primarily ER-negative (odds ratio, 1.93; 95% CI, 1.20 to 3.11 in NEJM 2022 study)	33471991; 33471974; 21980511; 22167183; 35039523; 30504931
RAD51D	2	Loss of function	602954	RAD51D	RAD51D breast	sequence variants	Diseases: Slight increased risk for hereditary BC, primarily ER-negative (odds ratio, 1.80; 95% CI, 1.11 to 2.93 in NEJM 2022 study)	33471991; 33471974; 30504931
RB1	2	Loss of function	614041	RB1	RB1 breast	sequence variants, other structural rearrangement	Therapy: acquired hormone resistance; resistance to CDK4/6 inhibitors. Diseases: TNBC, metastatic BC	31118521; 28027327; 27135926; 29236940; 35005994
RECQL	2	Loss of function	600537	RECQL	RECQL breast	sequence variants	Diseases: moderate evidence for BC risk.	30504931
RET	1	Gain of function	164761	RET	RET breast	fusion, amplification, altered expression	Therapy: FDA approved for RET fusion; overexpression associated with endocrine resistance. Diseases: ER-positive BC	30446652; 24559440; 24526731; 23650283
RICTOR	2	Gain of function	609022	RICTOR	RICTOR breast	amplification, altered expression	Therapy: possibly targetable with mTOR inhibitors; Diseases: TNBC	29790419; 32819718
RPS6KB1	2	Gain of function	608938	RPS6KB1	RPS6KB1 breast	amplification, altered expression	Therapy: amplification or overexpression may predict sensitivity to inhibitors of p70S6K signaling, as well as to inhibitors of upstream signaling, including mTOR and PI3K. Overexpression linked with resistance to radiation treatment.	31959810; 20953835
RUNX1	3	Other/Complex	151385	RUNX1	RUNX1 breast	sequence variants, altered expression, other structural rearrangement	Diseases: Lobular BC, ER positive luminal BC (tumor suppressor), TNBC (oncogenic via overexpression). Prognosis: higher expression predictive of decreased survival.	28455962; 29581836; 22722202
RUNX3	3	Loss of function	600210	RUNX3	RUNX3 breast	altered expression, epigenetic modification, other structural rearrangement, sequence variants	Prognosis: poor survival, correlates with recurrence. RUNX3 functions to inhibit YAP-mediated migration and stemness in breast cancer, together with RUNX1	28455962; 29581836; 22722202; 22275124; 37420018
SETD2	2	Loss of function	612778	SETD2	SETD2 breast	sequence variants	Diseases: recurrent in phyllodes tumor	26437033; 33844099; 33782741; 35691725
SF3B1	2	Gain of function	605590	SF3B1	SF3B1 breast	sequence variants	Diseases: TNBC, ER positive luminal BC, adenoid cystic carcinoma	26095796; 27135926; 22722193
SMARCA5	3	Gain of function	603375	SMARCA5	SMARCA5 breast	sequence variants, other structural rearrangement, altered expression	Diseases: invasive ductal carcinoma, adenoid cystic carcinoma. SMARCA5 regulates nucleosome repeat length.	26095796; 34736517; 25377162; 36231036; 36630954
SPEN	3	Loss of function	613484	SPEN	SPEN breast	sequence variants, altered expression	Diseases: altered in 1-2% of invasisive breast carcinoma (CBioPortal); recent evidence suggests SPEN acts as a tumor suppressor in ER-positive breast cancer and overexpressed SPEN sensitizes HR-positive breast cancer cells to the effects of tamoxifen; more mutations detected in patients with ER+/PR- breast cancer or detectable MRD	26297734; 28877752; 38049758; 38062709
STK11	2	Loss of function	602216	STK11	STK11 breast	sequence variants	Diseases: syndromic risk for hereditary BC and other cancers (Peutz-Jeghers syndrome) (high penetrance, but most mutations detected in tumors are somatic not germline). Lkb1 activates AMPK and negatively regulates the mTOR pathway in response to cellular energy levels. Therapy: may be responsive to mTOR inhibitors.	20301425; 33471991; 28900777; 15261145; 30504931
TACSTD2	2	Gain of function	137290	TACSTD2	TACSTD2 breast	altered expression	Diseases: mBC. Trop-2 is protein product of TACSTD2, and is expressed in the majority of breast cancers. Therapy: Trop-2 expression is targeted by antibody-drug conjugate (ADC) sacituzumab govitecan in TNBC and HR+, HER2- mBC previously treated with endocrine therapy, a CDK4/6 inhibitor, and a multiple lines of chemotherapy.	29989029; 25944802; 30786188; 39282896; [?remove 36194623]; 32946924; 35477165; 33882206; 34116144
TBX3	2	Gain of function	601621	TBX3	TBX3 breast	sequence variants, amplification, altered expression	Diseases: ER positive BC, Enriched in special subtypes including neuroendocrine tumors, lobular BC; metastatic breast cancer. Therapy: hormone resistance. TBX3 is one of several estrogen receptor transcriptional regulators also including MYC, CTCF, FOXA1.	26451490; 26579496; 30205045; 30655984
TERT	2	Gain of function	187270	TERT	TERT breast	amplification, sequence variants	Diseases: phyllodes tumor, more frequent in borderline and malignant tumors (promoter mut); carcinoma (TERT amplification), metaplastic carcinoma (promoter mutation)	29043292; 29100407; 23887589; 29946183
TOP2A	2	Gain of function	126430	TOP2A	TOP2A breast	amplification, sequence variants	Therapy: responsiveness to anthracycline inhibitors. Prognosis: increased TOP2A expression is an adverse prognostic indicator.	22578285; 32140564; 20038724; 21917518; 32780321; 35297009
TP53	2	Loss of function	191170	TP53	TP53 breast	sequence variants, other structural rearrangement, altered expression	Diseases: All subtypes; enriched in TNBC. Constitutional variants associated with syndromic risk for hereditary BC and other cancers (Li-Fraumeni syndrome). Prognosis: unfavorable. Therapy: mutations in TP53 may increase resistance to ionizing radiation therapy; therapies for TP53mut BC in development.	20301425; 33471991; 28027327; 32636452; 24803582; 14576853; 30504931
TRPS1	2	Other/Complex	604386	TRPS1	TRPS1 breast	altered expression	Diseases: BC all types, diagnostic utility in identifying breast origin (IHC marker), including TNBC where it is useful as GATA3 expression is usually absent. TRPS1 is a GATA gene family member and paralog of GATA3. Overexpression is observed in breast cancer and is of uncertain prognostic significance. Therapy: overexpression is linked to multidrug resistance in BC.	33011748; 39243111; 39181273; 32695669
TWIST1	3	Gain of function	601622	TWIST1	TWIST1 breast	amplification, altered expression	Diseases: breast cancer invasion and metastasis, basal-like breast cancer	17437280; 19373776; 15131050; 27412325; 29073077; 27524420; 38963044; 35843065; 38003483
ZNF217	2	Gain of function	602967	ZNF217	ZNF217 breast	amplification, other structural rearrangement, altered expression	Diseases: mutations in non-coding regions associated with BC in patients with African ancestry. Amplification (20q13). Poor prognosis associated with exon 4-skipping isoform (ZNF217-ΔE4). Associated with migration/invasion, EMT, and bone metastasis.	34836952; 17040570; 34277402; 22728437; 28207159
ZNF703	2	Gain of function	617045	ZNF703	ZNF703 breast	amplification	Diseases: ER positive BC and luminal B; Therapy: BC cell lines overexpressing ZNF703 may be more resistant to tamoxifen treatment; Prognosis: may be poor in some cases (part of 8p11.2 gain/amplification)	21328542; 21337521; 23991038; 24156016; 33389351

Abbreviations: BC, breast cancer. TNBC, triple negative breast cancer.

†Cancer Genomics Consortium Levels of Evidence

Level	Data Source(s)	Interpretation
1	Current professional guidelines (NCCN, WHO, etc). Genes targeted by FDA-approved drug. Multiple large studies in the peer-reviewed medical literature with consensus regarding clinical significance of the gene.	Strong evidence supporting clinical utility of variant(s) for diagnosis, selection of therapies, or predicting disease outcome
2	Clinical trials, large studies, case series in the peer-reviewed medical literature.	Recurrent abnormalities. Emerging evidence supporting clinical utility of gene variant(s) for diagnosis, selection of therapies, or predicting disease outcome.
3	Case reports or expert opinion	Unknown clinical significance
4	Published evidence indicating lack of pathogenicity of variant(s)	Benign or likely benign