ClinVar

Description

Variant summary: BRCA2 c.8420C>T (p.Ser2807Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251370 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8420C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, colorectal cancer, as well as in controls (Giannakis_2016, Oliver_2019, Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multple studies using HDR assay report the variant to be functional/neutral (Guidugli_2012, Richardson_2021, Hart_2019). The HDR assay qualifies as a standardized gold-standard assay on the basis of the updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) Working Group (Brnich_2019). ClinGen SVI now recognizes benign functional evidence as sufficient for likely benign (Tavtigian_2018). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Seven submitters classified the variant as VUS while two classified the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign.