ClinVar Genomic variation as it relates to human health

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, 31391288; 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.

proposed classification - variant undergoing re-assessment, contact laboratory

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). This haplotype was also detected in a pediatric patient with high-grade glioma (Crotty EE et al. J Neurooncol, 2020 Jul;148:607-617). 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.

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)

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, 34994648; 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 p.Arg1242Ser variant has been identified in 1/31406 chromosomes in the general population by the Genome Aggregation Database (gnomAD). It remains a possibility that p.Arg1242Ser and p.Leu1201Val variants in cis may act in synergy to adversely affect MSH6 protein function. However, different missense variants that alter arginine at codon 1242 (p.Arg1242His and p.Arg1242del) are known to be disease-causing, indicating the functional and clinical importance of arginine at this position (ClinVar variation ID: 140866 and 89450). Based on the available evidence, we conclude that the phenotype observed in individuals carrying the double mutant allele may be attributable to the p.Arg1242Ser variant, while the role of p.Leu1201Val variant in disease remains unclear. Therefore, this p.Arg1242Ser variant is classified as Likely Pathogenic.