ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.194C>T (p.Ser65Leu) (rs41294984)

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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 RCV000568962 SCV000669945 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000568962 SCV000911820 benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000160709 SCV000211340 uncertain significance not provided 2018-08-20 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.194C>T at the cDNA level, p.Ser65Leu (S65L) at the protein level, and results in the change of a Serine to a Leucine (TCA>TTA). This variant was observed in an individual with colon cancer diagnosed under the age of 55; however, analysis of this tumor revealed presence of MLH1, MSH2, and MSH6 proteins by immunohistochemistry and microsatellite stable histology (Barnetson 2008). MSH6 Ser65Leu 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, including 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 Ser65Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074698 SCV000107903 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Invitae RCV000524128 SCV000166215 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-17 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 65 of the MSH6 protein (p.Ser65Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs41294984, ExAC 0.02%). This variant has been reported in individuals affected with colorectal cancer (PMID: 18033691), as well as in healthy control individuals (PMID: 24728327). ClinVar contains an entry for this variant (Variation ID: 89234). 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. Furthermore, algorithms developed to predict the effect of missense changes in mismatch repair genes both predict that this variant is neutral (PMID: 22290698, 23621914). 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.

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