ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4819A>G (p.Ile1607Val) (rs200582465)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221891 SCV000273354 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000221891 SCV000903839 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-16 criteria provided, single submitter clinical testing
Counsyl RCV000031507 SCV000786415 uncertain significance Breast-ovarian cancer, familial 2 2018-05-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000221701 SCV000591928 uncertain significance not specified 2014-04-17 criteria provided, single submitter clinical testing
GeneDx RCV000657070 SCV000279511 uncertain significance not provided 2017-11-29 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4819A>G at the cDNA level, p.Ile1607Val (I1607V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). Using alternate nomenclature, this variant would be defined as/ has been previously published as BRCA2 5047A>G. This variant has been observed at a frequency of 1/319 in a cohort of unaffected women, but was absent from 645 breast cancer patients (Suter 2004). BRCA2 Ile1607Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile1607Val is located in the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Ile1607Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000233915 SCV000283250 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1607 of the BRCA2 protein (p.Ile1607Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs200582465, ExAC 0.02%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 37926). 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 valine 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000221701 SCV000600612 uncertain significance not specified 2017-03-10 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031507 SCV000054112 uncertain significance Breast-ovarian cancer, familial 2 2012-04-23 no assertion criteria provided clinical testing

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