Submissions for variant NM_000251.3(MSH2):c.2063T>G (p.Met688Arg)

dbSNP: rs63749993

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076376	SCV000107403	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524375	SCV000548177	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-08-01	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 688 of the MSH2 protein (p.Met688Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 10080150, 15075785, 20010080, 21225464, 21239990, 22739024). It is commonly reported in individuals of Canary Islander ancestry (PMID: 15075785, 20010080, 22739024). Invitae’s Lynch syndrome clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 1,370,736 individuals referred for testing at Invitae. ClinVar contains an entry for this variant (Variation ID: 90874). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 22739024). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491088	SCV000580468	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-10	criteria provided, single submitter	clinical testing	The p.M688R pathogenic mutation (also known as c.2063T>G), located in coding exon 13 of the MSH2 gene, results from a T to G substitution at nucleotide position 2063. The methionine at codon 688 is replaced by arginine, an amino acid with very few similar properties. This pathogenic mutation has been reported in multiple families with HNPCC/Lynch syndrome (Lin X et al. Dig. Dis. Sci. 1999 Mar; 44(3):553-9; Pastrello C et al. Genet. Med. 2011 Feb; 13(2):115-24). In one study, this pathogenic mutation was reported in five unrelated families from Spain that not only had tumors associated with Lynch syndrome, but also had numerous incidences of CNS tumors associated with Turcot syndrome or CMMR-D. In vitro functional assays indicated that the hMSH2(M688R)-hMSH6 heterodimer lacked normal ATP functions and inhibited MMR activity of the wild-type heterodimer (Martín-López JV et al. Carcinogenesis 2012 Sep; 33(9):1647-54). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as a pathogenic mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284172	SCV001469808	pathogenic	not provided	2019-11-12	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset. Segregation with disease in affected individuals from a single family. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353848	SCV000592530	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Met688Arg variant has been reported in the literature in 75/1312 proband chromosomes of individuals meeting the Amsterdam and Bethesda criteria for HNPCC (Ali 2012, Lin 1999, Martin-Lopez 2012, Medina-Arana 2006, Medina-Arana 2011, Pastrello 2011); it was not identified in any of the 320 control chromosomes tested. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs63749993), but no frequency information was provided, and so the prevalence of this variant in the population is not known. The p.Met688 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Met688Arg variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Functional assays have found the p.Met688Arg variant to defective in ATP processing functions, and that the hMSH2(M688R)–hMSH6 protein can functionally inhibit the wildtype hMSH2–hMSH6 during the mismatch excision process (Martin-Lopez 2012). In addition, HNPCC-associated tumors from carriers were MSI-H, MSH2 deficient by immunohistochemistry and exhibited loss of heterozygosity for the normal allele (Martin-Lopez 2012, Medina-Arana 2006, Medina-Arana 2011, Pastrello 2011), increasing the likelihood that this variant is pathogenic. In summary, based on the above information, this variant is classified as pathogenic.
GeneReviews	RCV001804825	SCV002054068	not provided	Lynch syndrome 1		no assertion provided	literature only