ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3226G>A (p.Val1076Ile) (rs431825304)

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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 RCV000222899 SCV000275335 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000588617 SCV000694680 uncertain significance not provided 2017-01-02 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3226G>A (p.Val1076Ile) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant. This variant is absent in 119346 control chromosomes from ExAC. This variant has been reported in HBOC or HBOC-related families/patients and individuals undergoing BRCA1/2 testing in literature (Kote-Jarai_2011, Peixoto_2014) as well as clinical databases (UMD, ClinVar) without strong evidence for pathogenicity. In two instances, this variant was found to co-occur with other deleterious variants [BRCA2 c.3159delA (p.Asp1054IlefsX6) (UMD) and BRCA2 p.Ser871X (internal sample)], strongly suggesting for a benign outcome. Two clinical diagnostic laboratories in ClinVar have classified this variant as uncertain significance, however without evidence to independently evaluate. Taken together, this variant is classified as VUS-possibly benign.
Invitae RCV000799401 SCV000939061 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1076 of the BRCA2 protein (p.Val1076Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family suspected to be affected with hereditary breast and/or ovarian cancer (PMID: 24916970), and an individual affected with prostate cancer (PMID: 21952622). It has also been observed in an individual referred for BRCA2 testing (PMID: 27633797). However, in that individual a pathogenic allele was also identified in BRCA2, which suggests that the c.3226G>A variant was not the primary cause of disease. In this literature, due to an apparent typographical error, these variants are indicated to occur in BRCA1 instead of BRCA2. ClinVar contains an entry for this variant (Variation ID: 96788). 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 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.
Sharing Clinical Reports Project (SCRP) RCV000082909 SCV000114983 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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