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
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 colorectal neoplasms 2020-10-20 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.
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.
Ambry Genetics RCV000568962 SCV000669945 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-28 criteria provided, single submitter clinical testing The p.S65L variant (also known as c.194C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 194. The serine at codon 65 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in an individual with colorectal cancer whose tumor was microsatellite stable and exhibited normal MLH1, MSH2, and MSH6 protein expression by IHC (Barnetson RA et al. Hum. Mutat. 2008 Mar;29:367-74). This alteration has been classified as likely benign using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson B et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson B et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000568962 SCV000911820 benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing

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