ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3232G>C (p.Val1078Leu) (rs587779932)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656897 SCV000149316 uncertain significance not provided 2018-01-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3232G>C at the cDNA level, p.Val1078Leu (V1078L) at the protein level, and results in the change of a Valine to a Leucine (GTA>CTA). This variant was observed in at least one individual with a personal history of breast and/or ovarian cancer undergoing whole exome sequencing (Maxwell 2016). MSH6 Val1078Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the ATPase domain (Warren 2007, Kansikas 2011). 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 MSH6 Val1078Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000168205 SCV000218870 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 1078 of the MSH6 protein (p.Val1078Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 127582). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115407 SCV000601563 uncertain significance not specified 2017-06-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567226 SCV000662383 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Counsyl RCV000662609 SCV000785254 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-06-13 criteria provided, single submitter clinical testing
Color RCV000567226 SCV000911606 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-06 criteria provided, single submitter clinical testing

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