BARD1 NM_000465.4:c.764A>G, Asn255Ser

Variant summary: BARD1 c.764A>G (p.Asn255Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 221662 control chromosomes, predominantly at a frequency of 0.00038 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.764A>G has been reported in the literature in individuals affected with breast cancer without strong evidence of causality (Adedokun_2020, Bishop_2020, Carvalho_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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: 23056176, 32039725, 31871109, 32866190). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 255 of the BARD1 protein (p.Asn255Ser). This variant is present in population databases (rs138904906, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 32039725, 32866190, 32885271). ClinVar contains an entry for this variant (Variation ID: 245891). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This missense variant replaces asparagine with serine at codon 255 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been identified in individuals affected with breast cancer (PMID: 31871109, 32039725, 32866190, 32885271). This variant has been identified in 8/253060 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.