ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2245G>A (p.Glu749Lys) (rs63751477)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076444 SCV000107472 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Abrogated function & 2 MSI-H tumours
Ambry Genetics RCV000218283 SCV000274701 likely pathogenic Hereditary cancer-predisposing syndrome 2018-06-05 criteria provided, single submitter clinical testing The p.E749K variant (also known as c.2245G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2245. The glutamic acid at codon 749 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in patients meeting Amsterdam and Bethesda criteria (Parc Y et al. J Med Genet. 2003 Mar;40(3):208-13; Mangold E et al. Int J Cancer. 2005 Sep 20;116(5):692-702). In one family meeting Amsterdam criteria, the proband was diagnosed with a microsatellite unstable (MSI-H) colorectal cancer at age 29y and had six family members diagnosed with an HNPCC-associated tumor (Ollila S et al. Gastroenterology. 2006 Nov;131(5):1408-17). In functional studies assessing repair activity, protein stability, mismatch binding, and ATP-catalyzed mismatch release activities, this alteration showed deficient repair and release activity (Ollila S et al. Gastroenterology. 2006 Nov;131(5):1408-17; Ollila S et al. Hum Mutat. 2008 Nov;29(11):1355-63). This amino acid position is highly conserved in available vertebrate species. 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 E et al. Hum Mutat. 2008 Jun;29(6):852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001062435 SCV001227235 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-08-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 749 of the MSH2 protein (p.Glu749Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 21120944, 12624141, 15849733, 21642682). ClinVar contains an entry for this variant (Variation ID: 90942). This variant has been reported to affect MSH2 protein function (PMID: 23690608, 21120944, 18470917, 18951462, 17101317, 30998989). 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.

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