GTS5:BRCA-related cancer predisposition syndrome (BRCA1, BRCA2): Difference between revisions
| [unchecked revision] | [unchecked revision] |
No edit summary |
No edit summary |
||
| Line 53: | Line 53: | ||
|Multiple variant types leading to '''loss of BRCA2 function''', resulting in defective '''homologous recombination–mediated DNA double-strand break repair''', genomic instability, and cancer susceptibility | |Multiple variant types leading to '''loss of BRCA2 function''', resulting in defective '''homologous recombination–mediated DNA double-strand break repair''', genomic instability, and cancer susceptibility | ||
|'''Autosomal dominant''' cancer predisposition with '''incomplete penetrance''' and variable expressivity; '''autosomal recessive''' when biallelic, causing '''Fanconi anemia subtype D1 (FA-D1)''' | |'''Autosomal dominant''' cancer predisposition with '''incomplete penetrance''' and variable expressivity; '''autosomal recessive''' when biallelic, causing '''Fanconi anemia subtype D1 (FA-D1)''' | ||
|Heterozygous pathogenic variants confer increased lifetime risk of '''female and male breast, ovarian, pancreatic, prostate, and melanoma''' cancers. Estimated female breast cancer risk ~'''45–70%''', ovarian cancer ~'''10–30%'''<ref name=":0" /><ref name=":1" /> . Founder mutations include '''c.5946delT (6174delT)''' in Ashkenazi Jewish populations<ref name=":0" /><ref name=":6">Oddoux C, Struewing JP, Clayton CM, Neuhausen S, Brody LC, Kaback M, Haas B, Norton L, Borgen P, Jhanwar S, Goldgar D, Ostrer H, Offit K. The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet. 1996 Oct;14(2):188-90. doi: 10.1038/ng1096-188. PMID: 8841192.</ref> . '''Large genomic rearrangements''' represent a clinically significant subset of pathogenic variants and may be missed by sequencing-only assays . Biallelic pathogenic variants result in '''FA-D1''', characterized by congenital anomalies, bone marrow failure, and early-onset malignancies | |Heterozygous pathogenic variants confer increased lifetime risk of '''female and male breast, ovarian, pancreatic, prostate, and melanoma''' cancers. Estimated female breast cancer risk ~'''45–70%''', ovarian cancer ~'''10–30%'''<ref name=":0" /><ref name=":1" /> . Founder mutations include '''c.5946delT (6174delT)''' in Ashkenazi Jewish populations<ref name=":0" /><ref name=":6">Oddoux C, Struewing JP, Clayton CM, Neuhausen S, Brody LC, Kaback M, Haas B, Norton L, Borgen P, Jhanwar S, Goldgar D, Ostrer H, Offit K. The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet. 1996 Oct;14(2):188-90. doi: 10.1038/ng1096-188. PMID: 8841192.</ref> . '''Large genomic rearrangements''' represent a clinically significant subset of pathogenic variants and may be missed by sequencing-only assays<ref name=":7">Sluiter MD, van Rensburg EJ. Large genomic rearrangements of the BRCA1 and BRCA2 genes: review of the literature and report of a novel BRCA1 mutation. Breast Cancer Res Treat. 2011 Jan;125(2):325-49. doi: 10.1007/s10549-010-0817-z. Epub 2010 Mar 16. PMID: 20232141.</ref> . Biallelic pathogenic variants result in '''FA-D1''', characterized by congenital anomalies, bone marrow failure, and early-onset malignancies<ref name=":8">Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet. 2007 Jan;44(1):1-9. doi: 10.1136/jmg.2006.043257. Epub 2006 Jul 6. PMID: 16825431; PMCID: PMC2597904.</ref><ref name=":9">Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D'Andrea AD. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002 Jul 26;297(5581):606-9. doi: 10.1126/science.1073834. Epub 2002 Jun 13. PMID: 12065746.</ref> | ||
|} | |} | ||
==Genetic Abnormalities: Somatic== | ==Genetic Abnormalities: Somatic== | ||
| Line 137: | Line 137: | ||
<ref name=":6" />Oddoux C, Struewing JP, Clayton CM, Neuhausen S, Brody LC, Kaback M, Haas B, Norton L, Borgen P, Jhanwar S, Goldgar D, Ostrer H, Offit K. The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet. 1996 Oct;14(2):188-90. doi: 10.1038/ng1096-188. PMID: 8841192. | <ref name=":6" />Oddoux C, Struewing JP, Clayton CM, Neuhausen S, Brody LC, Kaback M, Haas B, Norton L, Borgen P, Jhanwar S, Goldgar D, Ostrer H, Offit K. The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet. 1996 Oct;14(2):188-90. doi: 10.1038/ng1096-188. PMID: 8841192. | ||
<ref name=":7" />Sluiter MD, van Rensburg EJ. Large genomic rearrangements of the BRCA1 and BRCA2 genes: review of the literature and report of a novel BRCA1 mutation. Breast Cancer Res Treat. 2011 Jan;125(2):325-49. doi: 10.1007/s10549-010-0817-z. Epub 2010 Mar 16. PMID: 20232141. | |||
<ref name=":8" />Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet. 2007 Jan;44(1):1-9. doi: 10.1136/jmg.2006.043257. Epub 2006 Jul 6. PMID: 16825431; PMCID: PMC2597904. | |||
<ref name=":9" />Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D'Andrea AD. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002 Jul 26;297(5581):606-9. doi: 10.1126/science.1073834. Epub 2002 Jun 13. PMID: 12065746. | |||