ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.138C>G (p.His46Gln) (rs33946261)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
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.
Invitae RCV000076150 SCV000166262 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115501 SCV000172719 likely benign Hereditary cancer-predisposing syndrome 2018-12-13 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Does not segregate with disease in family study (genes with incomplete penetrance);Other data supporting benign classification
Color Health, Inc RCV000115501 SCV000537523 likely benign Hereditary cancer-predisposing syndrome 2017-08-29 criteria provided, single submitter clinical testing
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121555 SCV000696213 likely benign not specified 2019-02-14 criteria provided, single submitter clinical testing Variant summary: MSH2 c.138C>G (p.His46Gln) results in a non-conservative amino acid change located in the N-terminal domain (IPR007695) 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 0.00025 in 264460 control chromosomes (gnomAD and publication data), predominantly within the Non-Finnish European subpopulation at a frequency of 0.00047 in the gnomAD database, including 1 homozygote. This frequency is somewhat lower than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (0.00047 vs 0.00057), though the variant still might represent a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant has been identified in numerous patients with colorectal cancer (CRC), prostate cancer and ovarian cancer without strong evidence for causality (Barnetson_2008, Hampel_2005, Pal_2012, Grant_2015, Arora_2015, Lagerstedt-Robinson_2016, Maxwell_2016, Ghazani_2017, Raskin_2017, Rossi_2017, Velho_2018, Young_2018). In several studies, microsatellite stability in tumor tissues was assayed and found to be stable and immunohistochemical studies showed the presence of MSH2 (and MSH6) protein (Barnetson_2008, Hampel_2005, Arora_2015). 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 (Hampel_2005). In addition, one study reported the variant to not segregate with disease in a family, i.e. three affected individuals did not carry the variant, while three unaffected individuals carried the variant (Hansen_2017). An in vitro functional study demonstrated that the variant of interest does not impact mismatch repair activity (Houlleberghs_2016). Another study that was performed on lymphoblastoid cells from a sporadic CRC patient who carried the variant, found increased level of DNA damage after UV treatment (Arora_2015). Since the patient's tumor sample showed stable microsatellites and normal expression of mismatch repair (MMR) proteins, the authors postulated that beyond its function in MMR, this variant might predispose to DNA double-strand breaks by affecting homologous recombinational repair. Eight ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant, three times as likely benign and five times as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
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.
Mendelics RCV000664309 SCV000837815 uncertain significance Lynch syndrome 2018-07-02 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
Mendelics RCV000986643 SCV001135691 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000986643 SCV001302263 uncertain significance Lynch syndrome I 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ITMI RCV000121555 SCV000085749 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000148631 SCV000190346 uncertain significance Colorectal cancer 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354246 SCV001548810 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The MSH2 p.His46Gln variant was identified in 8 of 8869 proband chromosomes (frequency: 0.0009) from individuals or families with Lynch Syndrome, colorectal cancer, multiple adenomas, pancreatic cancer, or ovarian cancer and was identified in 1 of 3326 control chromosomes (frequency: 0.0003) from healthy individuals (Barnetson 2008, Fearnhead 2004, Grant 2015, Hampel 2005, Hansen 2017, Lagerstedt-Robinson 2016, Pal 2012, Rossi 2017). Segregation analysis of the variant in one family with colorectal cancer did not support pathogenicity as the variant was seen in both affected and unaffected family members (Hansen 2017). One study found the variant to be non-pathogenic using a site-specific mutagenesis screen (Houlleberghs 2016). The variant was identified in dbSNP (ID: rs33946261) as “With Likely benign, other allele”, ClinVar (classified as uncertain significance by an InSiGHT expert panel in 2015, Invitae, Color, and four other submitters; and as likely benign by GeneDx, Ambry Genetics, and one other submitter), UMD-LSDB (classified as UV), and Mismatch Repair Genes Variant Database. The variant was identified in control databases in 58 of 256068 chromosomes (1 homozygous) at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 55 (1 homozygous) of 115892 chromosomes (freq: 0.0005), African in 1 of 21856 chromosomes (freq: 0.00005), and Latino in 2 of 32620 chromosomes (freq: 0.00006); it was not observed in the “Other”, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.His46 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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