ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6439C>T (p.His2147Tyr) (rs587781476)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129424 SCV000184194 uncertain significance Hereditary cancer-predisposing syndrome 2013-12-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000129424 SCV000906140 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-15 criteria provided, single submitter clinical testing
GeneDx RCV000480281 SCV000571355 uncertain significance not provided 2018-01-16 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6439C>T at the cDNA level, p.His2147Tyr (H2147Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAC>TAC). Using alternate nomenclature, this variant would be defined as BRCA2 6667C>T. Although this variant has not, to our knowledge, been published in the literature as a germline variant, it has been reported as a somatic variant in an extra-uterine M?llerian carcinoma (Ritterhouse 2016). BRCA2 His2147Tyr was not observed in large population cohorts (Lek 2016). BRCA2 His2147Tyr 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 His2147Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000545796 SCV000635509 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-02-15 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 2147 of the BRCA2 protein (p.His2147Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 141075). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
True Health Diagnostics RCV000129424 SCV000787941 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-30 no assertion criteria provided clinical testing

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