ClinVar Genomic variation as it relates to human health

This variant is denoted BRCA2 c.6638C>T at the cDNA level, p.Ser2213Phe (S2213F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). Using alternate nomenclature, this variant would be defined as BRCA2 6866C>T. This variant has been observed in at least one individual with breast cancer (Li 2017). BRCA2 Ser2213Phe was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser2213Phe occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Ser2213Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 2213 of the BRCA2 protein (p.Ser2213Phe). This variant is present in population databases (rs75925841, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 26287763, 28664449, 35918668). This variant is also known as 6866C>T. ClinVar contains an entry for this variant (Variation ID: 219680). 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.

The p.S2213F variant (also known as c.6638C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 6638. The serine at codon 2213 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Li G et al. J Cancer Res Clin Oncol, 2017 Oct;143:2011-2024; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Zhang Y et al. BMC Cancer, 2022 Aug;22:842). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

Variant summary: BRCA2 c.6638C>T (p.Ser2213Phe) results in a non-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 1.2e-05 in 248306 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6638C>T has been reported in the literature in individuals affected with Breast Cancer (example, Pal 2015, Li 2017, Gao_2020) and in unaffected Chinese control populations from the 1000 Genomes project (example, Kwong_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been observed at our laboratory ( BRCA1 c.815_824dupAGCCATGTGG, p.Thr276fsX14), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.

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

This missense variant replaces serine with phenylalanine at codon 2213 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). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in an individual affected with breast cancer and a suspected hereditary breast and ovarian cancer family and in unaffected individual (PMID: 27157322, 28664449). This variant has been identified in 3/248306 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.