ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1967C>T (p.Thr656Ile)

gnomAD frequency: 0.00001  dbSNP: rs876660857
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001048220 SCV001212212 uncertain significance Hereditary breast ovarian cancer syndrome 2019-04-01 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 656 of the BRCA2 protein (p.Thr656Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV002416371 SCV002723580 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-26 criteria provided, single submitter clinical testing The p.T656I variant (also known as c.1967C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 1967. The threonine at codon 656 is replaced by isoleucine, an amino acid with 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV003141973 SCV003807212 uncertain significance Pancreatic cancer, susceptibility to, 2 2022-12-14 criteria provided, single submitter clinical testing ACMG classification criteria: PM2 moderated, BP4 supporting
University of Washington Department of Laboratory Medicine, University of Washington RCV002416371 SCV003846418 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).

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