ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.560T>C (p.Leu187Pro) (rs63751444)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076638 SCV000107673 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Color Health, Inc RCV000581973 SCV000690118 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000581973 SCV001186319 pathogenic Hereditary cancer-predisposing syndrome 2018-12-26 criteria provided, single submitter clinical testing The p.L187P pathogenic mutation (also known as c.560T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 560. The leucine at codon 187 is replaced by proline, an amino acid with similar properties. This mutation has been reported in families meeting Bethesda or Amsterdam criteria and segregated with disease in one family with Muire-Torre phenotype (Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702; Ollila S et al. Int. J. Oncol. 2006 Jan;28:149-53). Published structural analysis suggests that this alteration (L187P) structurally destabalizes the MSH2 protein resulting in reduced binding to MSH3 and MSH6 (Nielsen SV et al. PLoS Genet., 2017 Apr;13:e1006739). In addition, functional assays have shown that the L187P protein is MMR deficient (Ollila S et al. Int. J. Oncol. 2006 Jan;28:149-53; Ollila S et al. Gastroenterology 2006 Nov;131:1408-17; Martinez SL et al. Proc. Natl. Acad. Sci. U.S.A. 2010 Mar;107:5070-5). 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/]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001240116 SCV001413039 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-19 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 187 of the MSH2 protein (p.Leu187Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in many individuals affected with Lynch syndrome (LS) (PMID: 16327991, 18951462, 17101317, 15849733) and has also been reported to segregate with LS-associated cancer in the affected families (PMID: 16327991). ClinVar contains an entry for this variant (Variation ID: 91134). This variant has been reported to affect MSH2 protein function (PMID: 16327991, 18951462, 17101317, 28422960). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353422 SCV000592468 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The p.Leu187Pro has been previously has been previously reported by our laboratory in one family with Lynch related tumors and was demonstrated to segregate in three affected individuals and to result in MSH2 immuno-deficiency. In addition, this variant was shown to result in a loss of MSH2 expression by immunohistochemistry and was found to be completely deficient by in vitro MMR activity (Ollila_2006, Ollila_2008, Martinez_2009). One study also classified this variant as deleterious using the multivariate analysis of protein polymorphisms (MAPP)-mismatch repair (MMR) assay (Chao_2008), and a three-step functional analysis model compiling information from the literature has also implicated this as a clinically significant alteration (Kansikas_2010). Another variant at the same amino acid position (p.Leu187Arg) has been documented in the literature in a proband who was MSI +ve and had both colorectal and breast carcinoma (Peel_2000), increasing the likelihood that the p.Leu187Pro variant may have clinical significance. Based on the above information this variant is classified as PATHOGENIC.

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