ClinVar Genomic variation as it relates to human health

Variant summary: BRCA2 c.7706G>A (p.Gly2569Asp) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. This variant is also known as 7934G>A. The variant allele was found at a frequency of 4e-06 in 251340 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7706G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, and Familial adenomatous polyposis (examples: Park_BRCA_2017, Eoh_2018, Lee_2018, Momozawa_2018, Kim_2019) but it was also reported in unaffected controls (Dong_2021, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one co-occurrence with a pathogenic variant has been reported (BRCA1 c.3442delG, p.Glu1148ArgfsX7; Eoh_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.G2569D variant (also known as c.7706G>A), located in coding exon 15 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7706. The glycine at codon 2569 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported with a carrier frequency of 0.00014 in 7051 unselected breast cancer patients and not identified in female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration has also been reported in an individual with a personal history of epithelial ovarian cancer, detected in conjunction with a pathogenic truncating alteration in BRCA1 (Eoh KJ et al. Cancer Res Treat, 2018 Jul;50:917-925). This alteration was classified as likely benign by a multifactorial analysis that utilized data on co-occurrence, personal and family history, and tumor characteristics (Lee JS et al. J. Med. Genet., 2018 12;55:794-802). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

This missense variant replaces glycine with aspartic acid at codon 2569 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251340 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.

In the published literature, this variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMIDs: 28111427 (2017), 29020732 (2018), 30415210 (2018), 30287823 (2018), 31907386 (2020), 33471991 (2021)). This variant has also been reported in unaffected individuals (PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.000004 (1/251340 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2569 of the BRCA2 protein (p.Gly2569Asp). This variant is present in population databases (rs587781943, gnomAD 0.006%). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 28111427, 29020732, 30287823, 34063308). ClinVar contains an entry for this variant (Variation ID: 141695). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.

Observed in individuals with breast or ovarian cancer, and co-occurred with a BRCA1 pathogenic variant in one case (PMID: 28111427, 29020732, 30415210, 30287823, 31907386, 33471991); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7934G>A; This variant is associated with the following publications: (PMID: 29020732, 28111427, 30415210, 32467295, 12228710, 30287823, 31907386, 31269945, 33471991)