ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6691G>A (p.Ala2231Thr) (rs758379999)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166928 SCV000217747 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166928 SCV000912001 likely benign Hereditary cancer-predisposing syndrome 2016-02-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589983 SCV000694987 uncertain significance not provided 2017-02-10 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6691G>A (p.Ala2231Thr) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 4/5 in silico tools. The variant is located outside of some commonly known domains in BRCA2 protein (InterPro, UniPro). This variant is absent in 121158 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases, nor evaluated for functional impact by in vivo/vitro studies. A clinical diagnostic laboratory has reported this variant once in an individual undergoing BRCA1/2 testing without evidence to independently evaluate and has classified the variant as uncertain significance. Another amino acid change at this residue p.Ala2231Phe is classified as VUS in ClinVar by a lab. Based on the currently available information, this variant is classified as a variant of uncertain significance (VUS).
Invitae RCV000637506 SCV000758967 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 2231 of the BRCA2 protein (p.Ala2231Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 187220). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The threonine 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.

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