BRCA1 NM_007294.3:c.2155A>G, Lys719Glu

Variant summary: BRCA1 c.2155A>G (p.Lys719Glu) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be tolerated. The variant allele was found at a frequency of 2.7e-05 in 1461928 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database. Additionally, the variant was reported in 5/2559 African American women (i.e. with an allele frequency of about 0.001), who were older than age 70, and have never had cancer (in the FLOSSIES database), suggesting that the variant might be a benign polymorphism. c.2155A>G, has been reported in the literature in individuals affected with or without a family history of Breast and Ovarian Cancer (Judkins_2005, Pal_2015, Abe_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30883245, 16267036, 26287763, 15385441). ClinVar contains an entry for this variant (Variation ID: 37452). Based on the evidence outlined above, the variant was classified as likely benign.

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).