ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: 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 2021-12-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 1242 of the MSH6 protein (p.Arg1242Ser). This variant is present in population databases (rs587779285, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of Lynch syndrome, and has been frequently observed in cis with MSH6 c.3601C>G (p.Leu1201Val) (PMID: 29875428; Invitae). ClinVar contains an entry for this variant (Variation ID: 89449). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH6 protein function. 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: 17718861, 23729658, 24763289, 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 2019-04-22 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: none, 29875428)
Laboratory for Molecular Medicine,Mass General Brigham 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 2021-03-11 criteria provided, single submitter clinical testing This missense variant replaces arginine with serine at codon 1242 in the ATPase domain of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported to be in complete linkage disequilibrium with c.3601C>G (p.Leu1201Val)(ClinVar SCV000276654.6). This haplotype has been observed in multiple individuals affected with Lynch syndrome-associated cancers (PMID: 29875428, 31391288; O’Leary 2014; ClinVar variation ID: 89449), and in an individual affected with constitutional mismatch repair deficiency who carried a pathogenic MSH6 c.3434-2A>G variant on the different chromosome (Alshuaibi et al., ACMG 2016 poster). This variant has been identified in 1/31406 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg1242His and p.Arg1242del, are known to be disease-causing (ClinVar variation ID: 140866 and 89450), indicating the functional importance and clinical relevance of arginine at this position. Based on the available evidence, this variant is classified as Likely Pathogenic.

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