ClinVar

Description

Variant summary: BRCA2 c.9945delA (p.Glu3316AsnfsX2) results in a premature termination codon. This variant is located in close proximity to another variant suggested in the literature to be a polymorphism (c.9976A>T, p.Lys3326X; classified as normal variant in our internal database). Other truncations downstream of this position have been classified by our laboratory ranging from VUS to Normal (Possibly Normal (c.9997_9998delCT, p.Leu3333fsX4); VUS (c.10024G>T, p.Glu3342X); Normal (c.10095delinsGAATTATATCT, p.Ser3366fsX4). The variant allele was found at a frequency of 1.6e-05 in 254490 control chromosomes (gnomAD and publication data). Additionally, it is reported in NHLBI Exome Sequencing Project in homozygous state in two individuals of African American origin; however, data from this project are included in gnomAD database and no report of homozygous occurrences exists in the specific database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9945delA has been reported in the literature in individuals affected with breast cancer (Copson_2018, Walsh_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Experimental evidence evaluating an impact on protein function did not provide strong evidence for pathogenicity of this variant (the variant showed 63% homology directed repair capacity relative to the levels observed in wild type and also, displayed cisplatin sensitivity of 61% compared to the wild type in a cell survival assay, Mesman_2018). Seven ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.