ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3724C>A (p.Arg1242Ser) (rs587779285)

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Total submissions: 6
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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 2020-07-06 criteria provided, single submitter clinical testing The p.R1242S variant (also known as c.3724C>A), located in coding exon 8 of the MSH6 gene, results from a C to A substitution at nucleotide position 3724. The arginine at codon 1242 is replaced by serine, an amino acid with dissimilar properties. The p.L1201V variant (also known as c.3601C>G), located in coding exon 7 of the MSH6 gene, results from a C to G substitution at nucleotide position 3601. The leucine at codon 1201 is replaced by valine, an amino acid with highly similar properties. The p.L1201V and p.R1242S alterations have been observed to be linked in cis and in complete linkage disequilibrium (Ambry internal data). This haplotype has been observed in several individuals diagnosed with Lynch-related tumors in their 40-50s, including individuals who met Amsterdam criteria and with MSI-H colorectal tumors and/or loss of MSH6 on immunohistochemistry (O'Leary et al. Am. J. Digest. Dis. 2014;1(1):62-66; Ambry internal data). This haplotype has also been observed in conjunction with a mutation in MSH6 (c.3439-2A>G), in a girl with clinical features consistent with constitutional mismatch repair deficiency (CMMRD) syndrome (Ambry internal data). Based on internal structural analysis, this haplotype is more destabilizing than known likely pathogenic variants in the same domain. This amino acid position is highly conserved in available vertebrate species. The in silico predictions for p.L1201V and p.R1242S alterations are inconclusive and deleterious, respectively. Based on the majority of available evidence to date, this haplotype is likely to be pathogenic.
Invitae RCV000684809 SCV000551123 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-22 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 (ExAC no frequency). This variant has been reported in individual(s) in the Leiden Open-source Variation Database and in individuals with clinical features of Lynch syndrome, and has been observed to co-occur with MSH6 c.3601C>G (p.Leu1201Val) (PMID: 21520333, 29875428, 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 and their clinical significance is uncertain. This variant disrupts the p.Arg1242 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24763289, 23729658, 17718861, 24933100). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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
Color Health, Inc RCV000216969 SCV001344754 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-20 criteria provided, single submitter clinical testing

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