ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.138C>G (p.His46Gln) (rs33946261)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115501 SCV000172719 likely benign Hereditary cancer-predisposing syndrome 2017-12-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,Does not segregate with disease in family study (genes with incomplete penetrance),Co-occurence with mutation in same gene (phase unknown)
CSER_CC_NCGL; University of Washington Medical Center RCV000148631 SCV000190346 uncertain significance Colorectal cancer 2014-06-01 no assertion criteria provided research
Color RCV000115501 SCV000537523 likely benign Hereditary cancer-predisposing syndrome 2017-08-29 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764420 SCV000895477 uncertain significance Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000121555 SCV000149410 likely benign not specified 2018-01-05 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.
ITMI RCV000121555 SCV000085749 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000586635 SCV000696213 uncertain significance not provided 2017-07-14 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.138C>G (p.His46Gln) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution within the N-terminal DNA mismatch repair protein MutS domain (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in controls (ExAC and publication controls) with an allele frequency of 0.0003667 (31/84530 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), though the frequency in the European (Non-Finnish) subpopulation is nearly at this frequency in ExAC (0.000529). The variant has been identified in numerous patients with colorectal cancer and ovarian cancer without strong evidence for causality (e.g., Barnetson_2008; Fearnhead_2004; Grant_2015). In several studies, microsatellite stability in tumor tissues was assayed and found to be stable and immunohistochemical studies showed the presence of MSH2 protein (Barnetson_2008; Hampel_2005; Arora_2015). Additional functional studies suggest that the variant causes defective double strand DNA break repair (Arora_2015) but does not impact mismatch repair activity (Houlleberghs_2016). In one patient, MLH1 was found to be hypermethylated at its promoter. This decreases the likelihood of this variant being a cause of germline inherited cancer as MLH1 promoter hypermethylation is associated with sporadic cancers instead of inherited cancers. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as one of uncertain significance. Taken together, this variant is classified as "Variant of Uncertain Significance (VUS)."
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000664309 SCV000107166 likely benign Lynch syndrome 2018-12-19 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability <0.05
Invitae RCV000076150 SCV000166262 uncertain significance Hereditary nonpolyposis colon cancer 2018-05-31 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 46 of the MSH2 protein (p.His46Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is present in population databases (rs33946261, ExAC 0.05%), 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 (PMID: 8700523, 15872200, 18033691, 26344056, 27601186, 28195393, 28125075), ovarian cancer (PMID: 23047549), pancreatic cancer (PMID: 25479140) and multiple adenomatous polyps (PMID: 15520370), as well as in a family with suspected Lynch syndrome (PMID: 28874130). ClinVar contains an entry for this variant (Variation ID: 90654). 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: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000121555 SCV000539682 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: ClinVar: 5 labs classify as VUS, including expert panel. No new information suggesting disease-causing role since expert classification.
Mendelics RCV000664309 SCV000837815 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000664309 SCV000788241 likely benign Lynch syndrome 2018-04-26 criteria provided, single submitter research The MSH2 variant designated as NM_000251.2:c.138C>G (p.His46Gln) is classified as likely benign. This variant is listed in population databases and is found in approximately 1 out of 950 individuals of European ancestry, which is not consistent with the prevalence of Lynch syndrome. The variant has been seen in tumors with molecular phenotypes inconsistent with Lynch syndrome ( Based on in-silico scores the variant has a prior probability of pathogenicity of 10% or lower (Thompson et al., 2013, PMID:22949379). Cosegregation analysis of two observed families was performed using (Rañola et al, 2018, PMID:28965303) yielded a combined likelihood ratio of 1.52:1 for this variant explaining cancer in the families (Thompson, et al., 2003, PMID:2900794). However, Bayesian analysis integrating all data (Tavtigian et al, 2018, PMID:29300386) gave a less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MSH2 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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