Submissions for variant NM_000179.3(MSH6):c.3431T>G (p.Met1144Arg)

dbSNP: rs864622607

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001034622	SCV000261304	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-05	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1144 of the MSH6 protein (p.Met1144Arg). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 30877237; Invitae). 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. 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. ClinVar contains an entry for this variant (Variation ID: 220619).
Ambry Genetics	RCV000220316	SCV000276196	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-18	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	likely pathogenic	not provided	2022-12-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17531815, 21120944, 12019211, 30877237)
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 Diagnostics, LLC DBA Color Health	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.