ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1730T>C (p.Ile577Thr) (rs63749910)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076260 SCV000107280 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx RCV000212607 SCV000149417 likely benign not specified 2018-05-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000115508 SCV000186134 likely benign Hereditary cancer-predisposing syndrome 2018-09-20 criteria provided, single submitter clinical testing Other data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae RCV000524356 SCV000254392 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 577 of the MSH2 protein (p.Ile577Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs63749910, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in the literature in individuals affected with colorectal cancer and ovarian cancer (PMID: 16408224, 16736289, 19117025, 21056691, 22006311). ClinVar contains an entry for this variant (Variation ID: 41644). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000415673 SCV000493755 uncertain significance Lynch syndrome I 2016-03-30 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212607 SCV000539689 uncertain significance not specified 2017-01-25 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: Classified within the last year. This variant has been reported in 1 indidivual who did not have cancer, and 1 individual with CRC. The variant has a Max MAF of 0.02% in ExAC (14 alleles) and 0.03% in gnomAD (38 alleles). It is classified with 3 stars in ClinVar as Likely benign by an expert panel (InSiGHT) and Ambry, and VUS by GeneDx, Invitae, and Biesecker lab.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212607 SCV000601437 uncertain significance not specified 2017-02-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212607 SCV000696225 likely benign not specified 2019-05-02 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1730T>C (p.Ile577Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251570 control chromosomes, predominantly at a frequency of 0.00028 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (0.00015 vs 0.00057), allowing no conclusion about variant significance. The variant, c.1730T>C has been reported in the literature in individuals affected with colorectal cancer, endometrial cancer, ovarian cancer and hereditary diffuse gastric cancer (Spaepen_2006, Niessen_2006, Limburg_2011, Hampel_2006, South_2009, Hansford_2015) without strong evidence of causality. Many of these tumors show normal MSH2 expression by immunohistochemistry. In one patient absence of MLH1 (but normal expression of MSH2) protein was seen together with methylation of MLH1 promoter region suggestive of an alternative etiology and molecular basis of disease in this patient (Hampel_2006). Co-occurrence with another likely pathogenic/pathogenic variants have been reported (MUTYH c.36+1G>A in the literature and BRCA1 c.3005delA , p.Asn1002fsX22 at our laboratory) for this variant. These provide supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (uncertain significance (n=6) and one likely benign). An expert panel (InSight) classified this variant as likely benign based on a multifactorial probability model in 2013. Based on the evidence outlined above, the variant was re-classified as likely benign.
Mendelics RCV000076260 SCV000837837 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000115508 SCV000910631 likely benign Hereditary cancer-predisposing syndrome 2014-12-04 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034552 SCV001152279 likely benign not provided 2018-05-01 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034552 SCV000043342 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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