ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1222A>G (p.Met408Val)

dbSNP: rs1566223036
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000773547 SCV000907241 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-05 criteria provided, single submitter clinical testing This missense variant replaces methionine with valine at codon 408 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 not been reported in individuals affected with BRCA2-related disorders in the literature. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001246888 SCV001420280 uncertain significance Hereditary breast ovarian cancer syndrome 2021-10-19 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 628882). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 408 of the BRCA2 protein (p.Met408Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine.
University of Washington Department of Laboratory Medicine, University of Washington RCV000773547 SCV003849919 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Ambry Genetics RCV000773547 SCV004063132 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-17 criteria provided, single submitter clinical testing The p.M408V variant (also known as c.1222A>G), located in coding exon 9 of the BRCA2 gene, results from an A to G substitution at nucleotide position 1222. The methionine at codon 408 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. 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.

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