ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3601C>G (p.Leu1201Val) (rs182024561)

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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 RCV000220560 SCV000276654 likely pathogenic Hereditary cancer-predisposing syndrome 2017-08-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000767044 SCV000565849 uncertain significance not provided 2018-07-25 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3601C>G at the cDNA level, p.Leu1201Val (L1201V) at the protein level, and results in the change of a Leucine to a Valine (CTC>GTC). This variant has been identified in at least two individuals with a personal and/or family history colon cancer, with both individuals also carrying the MSH6 Arg1242Ser variant (O?Leary 2014, Turner 2018). MSH6 Leu1201Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Leu1201Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074891 SCV000108103 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000684810 SCV000551296 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 1201 of the MSH6 protein (p.Leu1201Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (rs182024561, ExAC no frequency). This variant has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). This individual, who also carried the MSH6 c.3724C>A (p.Arg1242Ser) variant, had colon, breast and uterine cancer. This variant has also been observed co-occurring with the c.3724C>A variant in several individuals and families with suspected Lynch syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 89423). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000483164 SCV000712852 uncertain significance not specified 2017-02-20 criteria provided, single submitter clinical testing The p.Leu1201Val variant in MSH6 has been reported in one individual with colore ctal cancer who also carried a second variant of uncertain significance in MSH6 (p.Arg1242Ser, O'Leary 2014). This variant was absent from large population stud ies. Computational prediction tools and conservation analysis suggest that the p .Leu1201Val variant may impact the protein, though this information is not predi ctive enough to determine pathogenicity. In addition, this variant was classifie d as a variant of uncertain significance on Sept 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108103.2). In summary, the clinical signifi cance of the p.Leu1201Val variant is uncertain.

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