Submissions for variant NM_000059.4(BRCA2):c.9700A>G (p.Met3234Val)

dbSNP: rs730881574

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160177	SCV000210515	uncertain significance	not provided	2019-11-29	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; 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 9928A>G; This variant is associated with the following publications: (PMID: 25348012)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552490	SCV000635755	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3234 of the BRCA2 protein (p.Met3234Val). 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: 182266). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs730881574, gnomAD 0.003%).
Ambry Genetics	RCV000568321	SCV000661212	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-11	criteria provided, single submitter	clinical testing	The p.M3234V variant (also known as c.9700A>G), located in coding exon 26 of the BRCA2 gene, results from an A to G substitution at nucleotide position 9700. The methionine at codon 3234 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly 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.
Color Diagnostics, LLC DBA Color Health	RCV000568321	SCV000684087	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000989092	SCV001139274	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193749	SCV001362826	uncertain significance	not specified	2020-11-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9700A>G (p.Met3234Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250412 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.9700A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four 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. Based on the evidence outlined above, the variant was classified as uncertain significance.