ClinVar Genomic variation as it relates to human health

The p.L824S variant (also known as c.2471T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 2471. The leucine at codon 824 is replaced by serine, an amino acid with dissimilar properties. This alteration was identified in an unselected Chinese individual diagnosed with breast cancer (Li G et al. J Cancer Res Clin Oncol, 2017 Oct;143:2011-2024). 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.

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

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: 133734). This missense change has been observed in individual(s) with breast and/ovarian cancer (PMID: 28664449, 31837001, 32068069). This variant is present in population databases (rs397507631, gnomAD 0.01%). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 824 of the BRCA2 protein (p.Leu824Ser).

Variant summary: BRCA2 c.2471T>C (p.Leu824Ser) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-06 in 237562 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2471T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, often reported as a VUS (examples: Li_2017, Kwong_2020, Guo_2020). These report(s) 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: 31837001, 32068069, 28664449). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories classified the variant as likely benign (n=1), uncertain significance (n=3), or likely pathogenic (n=1) . Based on the evidence outlined above, the variant was classified as uncertain significance.