ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3724C>A (p.Arg1242Ser) (rs587779285)

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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 RCV000216969 SCV000276653 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)
Invitae RCV000684809 SCV000551123 likely pathogenic Hereditary nonpolyposis colon cancer 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 1242 of the MSH6 protein (p.Arg1242Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (rs587779285, 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.3601C>G (p.Leu1201Val) variant, had colon, breast and uterine cancer. This variant has also been observed co-occurring with the c.3601C>G variant in several individuals and families with suspected Lynch syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 89449). 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. A different missense substitution at this codon (p.Arg1242His), along with deletion of the Arg1242 residue (p.Arg1242del), have been determined to be pathogenic (PMID: 24763289, 23729658, 17718861, 24933100). This suggests that the arginine residue is critical for MSH6 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000767045 SCV000565850 likely pathogenic not provided 2018-07-25 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3724C>A at the cDNA level, p.Arg1242Ser (R1242S) at the protein level, and results in the change of an Arginine to a Serine (CGT>AGT). This variant has been identified in at least two individuals with a personal and/or family history of colon cancer, with both individuals also carrying the MSH6 Leu1201Val variant (O?Leary 2014, Turner 2018). Of note, a different variant at the same residue, Arg1242His, has been observed in the homozygous state in two brothers with features of CMMRD (Grandaval 2013). In addition, a deletion of the Arg1242 residue (p.Arg1242del) has been reported in individuals with colorectal or uterine cancer demonstrating loss of MSH6 protein on immunohistochemistry (IHC) (Roncari 2007, Batte 2014). MSH6 Arg1242Ser 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, we consider MSH6 Arg1242Ser to be a likely pathogenic variant.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000486934 SCV000712855 uncertain significance not specified 2017-02-20 criteria provided, single submitter clinical testing The p.Arg1242Ser 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.Leu1201Val, O'Leary 2014) and was absent from large population studies. Compu tational prediction tools and conservation analysis suggest that the p.Arg1242Se r variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. Additionally, this variant was classified as a va riant of uncertain significance on Sept 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108131.2). In summary, the clinical significance of the p.Arg1242Ser variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000767045 SCV001134439 uncertain significance not provided 2018-10-25 criteria provided, single submitter clinical testing

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