ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2732T>G (p.Leu911Arg) (rs41295182)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524397 SCV000166278 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 911 of the MSH2 protein (p.Leu911Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is present in population databases (rs41295182, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with colorectal cancer and ovarian cancer (PMID: 18033691, 12537652, 23047549). ClinVar contains an entry for this variant (Variation ID: 91039). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000129717 SCV000184520 likely benign Hereditary cancer-predisposing syndrome 2018-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),Other data supporting benign classification,Does not segregate with disease in family study (genes with incomplete penetrance)
GeneDx RCV000589745 SCV000211223 uncertain significance not provided 2018-11-20 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2732T>G at the cDNA level, p.Leu911Arg (L911R) at the protein level, and results in the change of a Leucine to an Arginine (CTA>CGA). This variant has been reported in at least four individuals with colon cancer and one individual with epithelial ovarian cancer (Loader 2002, Barnetson 2008, Pal 2012, Ghazani 2017, Raskin 2017). Loader et al. (2002) concluded that MSH2 Leu911Arg was probably deleterious based on the microsatellite unstable (MSI-H) status observed in one individual?s colon tumor while Barnetson et al. (2008) classified this variant as benign based on computational models and lack of co-segregation. On functional interrogation, this variant did not result in 6TG-resistant colony formation, suggesting it does not affect mismatch repair function (Houlleberghs 2016). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies MSH2 Leu911Arg as a variant of uncertain significance (Thompson 2014). MSH2 Leu911Arg was observed at an allele frequency of 0.01% (16/126,192) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located within the helix-turn-helix domain and within the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Leu911Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Pathway Genomics RCV000172810 SCV000223776 uncertain significance Lynch syndrome I 2014-10-30 criteria provided, single submitter clinical testing
Color RCV000129717 SCV000292152 likely benign Hereditary cancer-predisposing syndrome 2016-07-29 criteria provided, single submitter clinical testing
Counsyl RCV000172810 SCV000488405 uncertain significance Lynch syndrome I 2016-03-17 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000235177 SCV000539686 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple reports describe as VUS/benign, ExAC: 0.02% (12/64562) European chromosomes
Integrated Genetics/Laboratory Corporation of America RCV000589745 SCV000696255 uncertain significance not provided 2016-08-08 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2732T>G (p.Leu911Arg) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 12/119698 control chromosomes at a frequency of 0.0001003, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). The variant has been reported in a colorectal cancer patient for which the variant did not segregate with the phenotype in the probands family (Barnetson_2008) and in an epithelial ovarian cancer patient for which no co-segregation or co-occurrence data was provided (Pal_2012). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
PreventionGenetics,PreventionGenetics RCV000589745 SCV000806035 uncertain significance not provided 2017-10-23 criteria provided, single submitter clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000760996 SCV000890911 uncertain significance Embryonal rhabdomyosarcoma; Ectomesenchymoma 2016-03-03 no assertion criteria provided clinical testing

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