Submissions for variant NM_000179.3(MSH6):c.3601C>G (p.Leu1201Val)

gnomAD frequency: 0.00001  dbSNP: rs182024561

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220560	SCV000276654	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-22	criteria provided, single submitter	clinical testing	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.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 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.
Invitae	RCV000684810	SCV000551296	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1201 of the MSH6 protein (p.Leu1201Val). This variant is present in population databases (rs182024561, 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.3724C>A (p.Arg1242Ser) (PMID: 29875428; Invitae). ClinVar contains an entry for this variant (Variation ID: 89423). 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. 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	RCV000767044	SCV000565849	uncertain significance	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	RCV000483164	SCV000712852	uncertain significance	not specified	2019-05-07	criteria provided, single submitter	clinical testing	The p.Leu1201Val variant in MSH6 has been reported in 2 individuals with colorectal cancer (O'Leary 2014, Turner 2018). It has also been identified in 1/15396 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Uncertain significance on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89423). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000767044	SCV001134435	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220560	SCV001342057	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-02	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1201 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.3724C>A (p.Arg1242Ser) (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: 89423), 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). The p.Leu1201Val variant has been identified in 1/31336 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.Leu1201Val variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV003466949	SCV004195833	likely pathogenic	Endometrial carcinoma	2023-02-21	criteria provided, single submitter	clinical testing