ClinVar Genomic variation as it relates to human health

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. 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. ClinVar contains an entry for this variant (Variation ID: 52265). This variant is also known as 7316A>G. This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 16949048, 17100994, 28664449, 29020732, 30702160). This variant is present in population databases (rs80358939, gnomAD 0.006%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2363 of the BRCA2 protein (p.Tyr2363Cys).

Variant summary: BRCA2 c.7088A>G (p.Tyr2363Cys) results in a non-conservative amino acid change in the encoded protein sequence outside of any known functional domain or repeat. 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 4.1e-06 in 1/246216 control chromosomes (East Asians: 1/17244 chrs tested). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7088A>G has been reported in the literature in individuals of East Asian descent affected with Breast and/or Ovarian Cancer (Kim 2006, Han 2006, Eoh 2017, Li 2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported (UMD database: BRCA1 c.1067delA , p.Gln356fsX18), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as 7316A>G; Observed in individuals with breast or ovarian cancer (Han 2006, Kim 2006, Li 2017, Eoh 2018); This variant is associated with the following publications: (PMID: 17100994, 28664449, 31825140, 29020732, 30702160, 16949048, 31131967, 25348012)

This missense variant replaces tyrosine with cysteine at codon 2363 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 16949048, 17100994, 28664449). This variant has been identified in 1/251020 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.

This missense variant replaces tyrosine with cysteine at codon 2363 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 16949048, 17100994, 28664449). This variant has been identified in 1/251020 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.

The p.Y2363C variant (also known as c.7088A>G), located in coding exon 13 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7088. The tyrosine at codon 2363 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in multiple Asian individuals diagnosed with breast and/or ovarian cancer (Han SH et al. Clin. Genet. 2006; 70:496-501; Kim BY et al. Biochem. Biophys. Res. Commun. 2006;349:604-610; Eoh KJ et al. Cancer Res Treat 2017 Sep; Li G et al. J Cancer Res Clin Oncol, 2017 Oct;143:2011-2024; Wang J et al. Cancer Med, 2019 May;8:2074-2084). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.