ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1223T>C (p.Met408Thr)

dbSNP: rs1057517562
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000412475 SCV000488535 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2016-04-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV001010412 SCV001170611 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-13 criteria provided, single submitter clinical testing The p.M408T variant (also known as c.1223T>C), located in coding exon 9 of the BRCA2 gene, results from a T to C substitution at nucleotide position 1223. The methionine at codon 408 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001850978 SCV002177663 uncertain significance Hereditary breast ovarian cancer syndrome 2024-03-19 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 408 of the BRCA2 protein (p.Met408Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with esophageal cancer (PMID: 22126563). ClinVar contains an entry for this variant (Variation ID: 371837). 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV001010412 SCV003849920 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).
All of Us Research Program, National Institutes of Health RCV000412475 SCV004829711 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2023-08-15 criteria provided, single submitter clinical testing

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