ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3431T>G (p.Met1144Arg) (rs864622607)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001034622 SCV000261304 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-03-07 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 1144 of the MSH6 protein (p.Met1144Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 220619). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000220316 SCV000276196 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-21 criteria provided, single submitter clinical testing The p.M1144R variant (also known as c.3431T>G), located in coding exon 5 of the MSH6 gene, results from a T to G substitution at nucleotide position 3431. The methionine at codon 1144 is replaced by arginine, an amino acid with similar properties. This alteration has been observed in multiple individuals whose personal and/or family histories are consistent with MSH6-associated disease (Pearlman R et al. J. Med. Genet. 2019 Jul;56:462-470; Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability of the ATPase domain (Warren JJ et al. Mol. Cell. 2007 May;26:579-92, Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000482863 SCV000566785 uncertain significance not provided 2016-09-13 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3431T>G at the cDNA level, p.Met1144Arg (M1144R) at the protein level, and results in the change of a Methionine to an Arginine (ATG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Met1144Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Met1144Arg occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located within the ATP-binding motif and the MutS domain V (Kariola 2002, Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Met1144Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington RCV000206842 SCV000788251 likely pathogenic Lynch syndrome 2018-02-07 criteria provided, single submitter clinical testing The MSH6 has been previously reported as a germline variant of uncertain significance in two patients with reported hereditary cancer-prediposing syndrome and Lynch syndrome. The variant occurs at a position that is evolutionarily conserved, and is not in the Insight database. One observed patient with constitutional MSH6 p.M1144R had two malignancies with isolated loss of MSH6 on IHC. Testing performed on colon tumor tissue of this patient supports that this variant is pathogenic. Specifically one heterozygous somatic pathogenic mutation in MSH6 was observed with the p.M1144R variant.
Color Health, Inc RCV000220316 SCV001735477 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-01 criteria provided, single submitter clinical testing This missense variant replaces methionine with arginine at codon 1144 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 in multiple individuals affected with Lynch Syndrome (ClinVar variation ID: 220619; communications with external laboratories). In three of these individuals, immunohistochemistry has shown the lack of MSH6 protein expression in tumors. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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