Submissions for variant NM_000059.4(BRCA2):c.7954G>A (p.Val2652Met)

dbSNP: rs1466452770

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529990	SCV000635621	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2652 of the BRCA2 protein (p.Val2652Met). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer, prostate cancer (PMID: 21520333, 34178674, 34242281). ClinVar contains an entry for this variant (Variation ID: 462460). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA2 function (PMID: 29394989, 29884841, 29988080). This variant disrupts the p.Val2652 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 34218100, 35464868; external communication). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Color Diagnostics, LLC DBA Color Health	RCV000580117	SCV000683920	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765139	SCV000896365	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321652	SCV004027477	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001529372	SCV004234657	uncertain significance	not provided	2023-03-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004568788	SCV005059189	uncertain significance	Familial cancer of breast	2023-11-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580117	SCV005102196	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-09	criteria provided, single submitter	clinical testing	The p.V2652M variant (also known as c.7954G>A), located in coding exon 16 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7954. The valine at codon 2652 is replaced by methionine, an amino acid with highly similar properties. This alteration has been shown to be neutral in homology-directed DNA repair (HDR) assays (Hart SN et al. Genet. Med., 2019 01;21:71-80; Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248). This variant was found to be functionally intermediate in a BRCA2-null mouse embryonic stem cell complementation assay, a homology-directed repair assay, and a cisplatin sensitivity assay (Mesman RLS et al. Genet Med, 2019 Feb;21:293-302). This alteration was also classified as benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence, and tumor pathology data (Caputo SM et al. Am J Hum Genet, 2021 Oct;108:1907-1923). 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 well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529372	SCV001742701	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001529372	SCV001799880	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001529372	SCV001906183	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529372	SCV001959525	uncertain significance	not provided		no assertion criteria provided	clinical testing