Submissions for variant NM_000059.4(BRCA2):c.8091C>A (p.Ser2697Arg)

dbSNP: rs140782158

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586424	SCV000695125	uncertain significance	not provided	2017-03-30	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.8091C>A (p.Ser2697Arg) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution. The variant lies within the BRCA2 oligonucleotide/oligosaccharide-binding 1 domain and the nucleic acid-binding OB-fold domain (InterPro), and 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent from the large control database ExAC (0/121358 control chromosomes). To our knowledge, the variant of interest has not been reported in affected individuals via publications or reputable databases/clinical diagnostic laboratories, nor has it been evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001050615	SCV001214733	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 2697 of the BRCA2 protein (p.Ser2697Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 34178674). ClinVar contains an entry for this variant (Variation ID: 495504). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV002420558	SCV002678516	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-03	criteria provided, single submitter	clinical testing	The p.S2697R variant (also known as c.8091C>A), located in coding exon 17 of the BRCA2 gene, results from a C to A substitution at nucleotide position 8091. The serine at codon 2697 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified within a cohort of 874 unrelated Italian breast or ovarian cancer patients undergoing genetic testing based on suspicion for HBOC (Fanale D et al. Front Oncol, 2021 Jun;11:682445). 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.
Color Diagnostics, LLC DBA Color Health	RCV002420558	SCV004362731	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-24	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 2697 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 an individual affected with breast cancer with a family history of breast and/or ovarian cancer (PMID: 34178674). This variant has not been identified 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.