ClinVar Genomic variation as it relates to human health

Variant summary: BRCA2 c.623T>G (p.Val208Gly) results in a non-conservative amino acid change in the encoded protein sequence. 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 3.6e-05 in 250830 control chromosomes, predominantly at a frequency of 0.00049 within the East Asian 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.623T>G has been reported in the literature in individuals of East Asian ethnicities affected with and/or undergoing genetic testing for Breast And Ovarian Cancer (example, Nakamura_2013, Arai_2018, Kim_2017, Takeuchi_2018, Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (example, Ikegami_2020). These results showed no damaging effect of this variant on homology directed repair (HDR) based on lack of sensitivity to platinum-based chemotherapies and poly (ADP-Ribose) polyperase inhibitors. HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Richardson_2021 citing Tavtigian_2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely benign.

The frequency of this variant in the general population, 0.00049 (9/18390 chromosomes in East Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 24249303 (2015), 27124784 (2016)). It was identified in large screening studies (PMID: 29176636 (2018), 32467295 (2020)), as well as in large breast cancer association studies in both cases and controls (PMID: 30287823 (2018), 33471991 (2021), https://databases.lovd.nl/shared/variants/BRCA2). It was also analyzed as likely neutral in a multifactorial analysis (PMID: 27124784 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Observed in individuals with breast and other cancers (Nakamura 2015, Park 2016, Momozawa 2018, Takeuchi 2018, Kim 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 851T>G; This variant is associated with the following publications: (PMID: 24249303, 23704879, 23983145, 27124784, 26761715, 26913838, 29338689, 30415210, 30287823, 29802286, 29176636, 32908793, 33078592, 33875706)