ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2848G>A (p.Val950Ile) (rs775903570)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213594 SCV000276008 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000238624 SCV000296491 uncertain significance Breast-ovarian cancer, familial 2 2016-06-18 criteria provided, single submitter clinical testing
Invitae RCV000472527 SCV000549836 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 950 of the BRCA2 protein (p.Val950Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs775903570, ExAC 0.01%). This variant has been reported in an individual affected with early-onset breast cancer (PMID: 17972177). ClinVar contains an entry for this variant (Variation ID: 231995). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
GeneDx RCV000478603 SCV000564771 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2848G>A at the cDNA level, p.Val950Ile (V950I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). Using alternate nomenclature, this variant has been previously published as BRCA2 3076G>A in at least one individual with early-onset breast cancer (Purnomosari 2007). BRCA2 Val950Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Val950Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000238624 SCV000786571 uncertain significance Breast-ovarian cancer, familial 2 2018-05-30 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769689 SCV000901102 uncertain significance Breast and/or ovarian cancer 2016-12-02 criteria provided, single submitter clinical testing

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