Submissions for variant NM_000251.3(MSH2):c.1759G>C (p.Gly587Arg)

dbSNP: rs63751140

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076270	SCV000107290	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration (full inactivation of variant allele)
Invitae	RCV000700587	SCV000829346	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-10	criteria provided, single submitter	clinical testing	This sequence change affects codon 587 of the MSH2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MSH2 protein. This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 20587412, 21642682, 22067334, 27601186). ClinVar contains an entry for this variant (Variation ID: 90771). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). Experimental studies have shown that this variant does not substantially affect MSH2 function (PMID: 33357406). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18561205; Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002408594	SCV002716200	pathogenic	Hereditary cancer-predisposing syndrome	2018-12-15	criteria provided, single submitter	clinical testing	The c.1759G>C pathogenic mutation (also known as p.G587R), located in coding exon 11 of the MSH2 gene, results from a G to C substitution at nucleotide position 1759. The amino acid change results in glycine to arginine at codon 587, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in multiple Lynch syndrome families (Sjursen W et al. J. Med. Genet., 2010 Sep;47:579-85; Bonadona V et al. JAMA, 2011 Jun;305:2304-10; Hagen CE et al. Am. J. Surg. Pathol., 2011 Dec;35:1902-5; Hansen MF et al. Mol Genet Genomic Med, 2014 Mar;2:186-200). Hagen et al. reported this alteration in an individual's colon tumor which showed absent MLH1/MSH2 protein expression and was positive for MLH1 promoter hypermethylation. The proband met Amsterdam II criteria and the c.1759G>C alteration was subsequently identified in the proband's germline. Sjursen et al. reported this alteration in an individual with colon cancer diagnosed under age 50 which showed absent MSH2 protein expression; further RT-PCR patient RNA studies demonstrated out-of-frame skipping of exon 11, resulting in a frameshift and premature truncation. Tournier et al. performed splicing analyses using a pCAS mini-gene in HeLa cells and also demonstrated exon 11 skipping (Tournier I et al. Hum. Mutat., 2008 Dec;29:1412-24). In addition, this mutation was identified as somatic in an individual with MSH2 absent colorectal cancer (Yuen ST et al. Oncogene 2002 Oct;21:7585-92). 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 on species alignment. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by BDGP; however, direct evidence is unavailable. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003452855	SCV004188965	pathogenic	Lynch syndrome 1	2023-08-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18561205].