ClinVar

Description

Variant summary: PALB2 c.3056T>C (p.Val1019Ala) results in a non-conservative amino acid change located in the WD40 domain that binds to the N-terminus of BRCA2 (IPR031920). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251450 control chromosomes (gnomAD), exclusively found in the African subpopulation with a frequency of 0.00031 (5/16256). In addition, this variant has been reported in 4/2559 African American women who are older than age 70 and cancer free (in the FLOSSIES database), supporting a benign role for the variant. c.3056T>C has been also reported in the literature in individuals affected with breast or ovarian cancer (Zheng_2012, Lu_2015) and in at least one individual with advanced cancer, type not specified (Mandelker_2017), but without strong evidence for causality. Therefore these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variant(s) have been reported (PALB2 c.1479delC (p.Thr494LeufsX67) in an internal LCA sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.