ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.3501A>G (p.Ile1167Met)

dbSNP: rs1593899752
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001020470 SCV001181955 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-12 criteria provided, single submitter clinical testing The p.I1167M variant (also known as c.3501A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3501. The isoleucine at codon 1167 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported with a carrier frequency of 1 in 7,051 unselected breast cancer patients and 0 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV001020470 SCV003846655 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).
Labcorp Genetics (formerly Invitae), Labcorp RCV003645141 SCV004551696 uncertain significance Hereditary breast ovarian cancer syndrome 2023-12-06 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1167 of the BRCA2 protein (p.Ile1167Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 823859). 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.

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