ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1094C>T (p.Pro365Leu) (rs730881578)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568907 SCV000668691 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000160181 SCV000210524 uncertain significance not provided 2018-11-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1094C>T at the cDNA level, p.Pro365Leu (P365L) at the protein level, and results in the change of a Proline to a Leucine (CCA>CTA). Using alternate nomenclature, this variant would be defined as BRCA2 1322C>T. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Pro365Leu 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 Pro365Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000459920 SCV000549794 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-26 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 365 of the BRCA2 protein (p.Pro365Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs730881578, ExAC <0.01%) but has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182270). 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.

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