GTS5:PALB2-related cancer predisposition syndrome (PALB2): Difference between revisions

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-|''PALB2''||SNVs (frameshift, nonsense, missense, splice site, synonymous splice mutations); CNVs (inactivating deletions or duplications)||Multiple variant types leading to loss of function||Autosomal dominant, ~35-60% penetrance for carriers. Autosomal recessive, Fanconi anemia (FA) subtype N, 100% penetrance.
+|''PALB2''||SNVs (frameshift, nonsense, canonical splice site, missense with loss of function, synonymous variants affecting splicing); CNVs (inactivating deletions or duplications).||Loss of function variants disrupt PALB2 mediated homologous recombination DNA repair through impaired BRCA1 BRCA2 interaction and defective RAD51 recruitment, resulting in homologous recombination deficiency and genomic instability.||Autosomal dominant cancer predisposition with moderate to high penetrance for breast cancer (~35-60%, modified by family history); Autosomal recessive inheritance causes Fanconi anemia, complementation group N (FA-N) with high penetrance.
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+|Germline pathogenic variants are predominantly loss-of-function (frameshift, nonsense, splice site)<ref name=":0" /><ref name=":1" /><ref name=":2" />. Several founder mutations have been reported, including c.1592delT in Finnish populations and recurrent truncating variants in European ancestry cohorts<ref name=":3" /><ref name=":6" />. Missense variants are less common and require functional and/or segregation evidence for classification<ref name=":2" /><ref name=":4" />. CNVs involving partial or whole-gene deletions account for a minority of pathogenic alleles but are clinically significant<ref name=":4" /><ref name=":5" />. Biallelic pathogenic variants cause Fanconi anemia subtype N, characterized by childhood onset bone marrow failure, developmental anomalies, and early onset malignancies<ref name=":2" />. PALB2 associated tumors share molecular features with BRCA-associated cancers and may demonstrate sensitivity to DNA damaging agents and PARP inhibitors<ref name=":2" /><ref name=":5" /><ref name=":8" />.
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