Submissions for variant NM_000251.3(MSH2):c.435T>G (p.Ile145Met)

gnomAD frequency: 0.00031  dbSNP: rs63750124

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588226	SCV000149441	likely benign	not provided	2021-09-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32075053, 31159747, 20176959, 26333163, 26096739, 28874130, 26332594, 24040339, 21788563, 17192056, 24933000, 20007843, 27328445, 21120944, 25133505, 12624141, 22581703, 12522549, 17720936, 25637381, 15254659, 16736289, 16451135, 15855432, 30238922)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085983	SCV000166282	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115532	SCV000187599	likely benign	Hereditary cancer-predisposing syndrome	2020-04-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212585	SCV000539684	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 papers classified as non-pathogenic, ExAC: 0.1% (38/66740) European chromosomes
Genetic Services Laboratory, University of Chicago	RCV000212585	SCV000595830	uncertain significance	not specified	2016-06-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212585	SCV000601480	benign	not specified	2021-08-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212585	SCV000696268	likely benign	not specified	2023-11-10	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.435T>G (p.Ile145Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 251922 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.00049 in the gnomAD database. Both of these frequencies are slightly lower than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00057), allowing no conclusion about variant significance. c.435T>G has been reported in the literature in individuals affected with Nonpolyposis Colorectal Cancer, where co-segregation with the disease was observed in at least two families (e.g., Parc 2003, Spaepen 2006). However, in these studies, not all MMR genes were analyzed and the possibility of other deleterious variants contributing to the disease phenotype cannot be excluded. Some of the reported patients have also carried other MSH6 variants (such as L1354Q; classified as VUS by InSiGHT), and the possibility of compound pathogenicity was suggested by the authors (e.g. Kariola 2003). This variant has been observed in a cohort of breast cancer patients as well as unaffected controls (e.g., Dorling_2021). These reports therefore do not provide unequivocal conclusions about association of the variant with Nonpolyposis Colorectal Cancer. However, a breast cancer patient was reported to carry the variant of interest as well as the variant PALB2 c.38_39insG/p.K14fs*29 (p.K14fs*29; Spugnesi_2016), providing supporting evidence for a benign role. Multiple publications have reported experimental evidence evaluating an impact on protein function, and demonstrated the variant results in preserved MSH2-MSH6 interaction and proficient MMR activity, further supporting a benign classification (e.g., Kariola 2003, Gammie 2007, Kansikas 2011, Kantelinen 2012). Multiple submitters have reported this variant to ClinVar after 2014 with conflicting assessments (VUS, n = 12; likely benign, n = 5; benign, n = 3). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000662480	SCV000784978	uncertain significance	Lynch syndrome 1	2017-02-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528278	SCV000806042	uncertain significance	MSH2-related disorder	2023-02-06	criteria provided, single submitter	clinical testing	The MSH2 c.435T>G variant is predicted to result in the amino acid substitution p.Ile145Met. This variant has been reported in individuals with hereditary non-polyposis colorectal cancer (Parc et al. 2003. PubMed ID: 12624141; Kariola et al. 2003. PubMed ID: 12522549; Kurzawski et al. 2006. PubMed ID: 16451135) and in one family with suspected Lynch syndrome (Rossi et al. 2017. PubMed ID: 28874130). In at least one case, microsatellite instability (an indicator of defective mismatch repair) and absence of MLH1 protein was also reported along with this variant (Pinol et al. 2005. PubMed ID: 15855432). A second variant in MSH6 was identified in a familial study suggesting digenic inheritance, but neither the MSH2 c.435T>G variant nor the second MSH6 variant impacted mismatch repair (Kariola et al. 2003. PubMed ID: 12522549). An independent functional study in yeast of the MSH2 p.Ile145Met change also revealed no difference in protein activity compared to the wild type (Gammie et al. 2007. PubMed ID: 17720936). This variant has conflicting interpretations in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/91097/). This variant is reported in 0.046% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47637301-T-G). Taken together, we suspect this variant to be benign, although at this time this variant’s clinical significance is uncertain.
GeneKor MSA	RCV000115532	SCV000822053	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764421	SCV000895478	uncertain significance	Lynch syndrome 1; Mismatch repair cancer syndrome 1; Muir-Torré syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115532	SCV000910574	likely benign	Hereditary cancer-predisposing syndrome	2015-11-05	criteria provided, single submitter	clinical testing
Mendelics	RCV000662480	SCV001135702	uncertain significance	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000662480	SCV001297028	uncertain significance	Lynch syndrome 1	2019-02-21	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262752	SCV001440734	uncertain significance	Breast carcinoma	2019-01-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000588226	SCV002009327	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798267	SCV002042109	uncertain significance	Breast and/or ovarian cancer	2023-06-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588226	SCV002498555	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	MSH2: BP4
Sema4, Sema4	RCV000115532	SCV002534522	likely benign	Hereditary cancer-predisposing syndrome	2021-01-18	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662480	SCV004018362	benign	Lynch syndrome 1	2023-03-22	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212585	SCV004243543	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115532	SCV005045451	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-12	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148628	SCV000190343	likely benign	Colorectal cancer, non-polyposis	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358588	SCV001554370	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Ile145Met variant was identified in 2 of 628 proband chromosomes (frequency: 0.003) from individuals or families with hereditary non-polyposis colorectal cancer or renal cell carcinoma (Spaepen 2006, Rubio-Del-Campo 2008). The variant was also identified in dbSBP (ID: rs63750124) classified as “With Uncertain significance”, ClinVar (1x benign: Invitae; 2x likely benign: Ambry Genetics, University of Washington Medical Center; 3x uncertain signirnficance: InSiGHT, GeneDx, Partners HealthCare), UMD-LSDB (biological significance: unclassified/unknown variant), Insight Colon Cancer Gene Variant Database (28 entries, class 3, uncertain significance), Mismatch Repair Genes Variant Database (5 references) databases. The variant was not identified in Genesight-COGR, MutDB, Zhejiang Colon Cancer Database, Insight Hereditary Tumors Database, or COSMIC databases. The variant was identified by our laboratory in 1 individual with endometrial cancer with MSH2/MSH6 deficiency by IHC. The variant was identified in control databases in 82 of 277196 chromosomes at a frequency of 0.0003 in the following populations: European (Non-Finnish) in 57 of 126682 chromosomes (freq. 0.00045), Latino in 12 of 34418 chromosomes (freq. 0.0003), European (Finnish) in 5 of 25792 chromosomes (freq. 0.0002), African in 3 of 24038 chromosomes (freq. 0.0001), and South Asian in 1 of 30782 chromosomes (freq. 0.00003), and other in 4 of 6466 chromosomes (freq. 0.0006) but was not seen in Ashkenazi Jewish and East Asian populations, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Functional studies using combined co-immunoprecipitation/ Western blot analysis shows this variant combined with wild type MSH6 actually increases protein translation, and the protein demonstrates an increased proportion of the MSH2 component. In addition, a MMR functional assay demonstrates that this variant is as functional as wild type protein, suggesting that, provided that protein levels are adequate, this variant is non-pathogenic (Kariola 2003). A yeast MMR assay demonstrates this variant retains 89% activity relative to wild type, supporting a non-pathogenic classification (Gammie 2007). A review of prior studies finds this variant to be non-pathogenic by MMR assay, in silico analysis, expression and interaction analysis, though it is noted that this variant has been found in carriers of other MMR gene variations (Kansikas 2010). Expression of MSH2 protein is demonstrated to be present by IHC in a non-Amsterdam criteria/non-Bethesda Guidelines patient with this variant (Pinol 2005). The p.Ile145Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. This residue is not located in an MSH2-MSH6 interaction region (Wielders 2013). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located within the DNA mismatch repair protein MSH2 functional domain, increasing the likelihood that it may have clinical significance. 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000588226	SCV001964952	likely benign	not provided		no assertion criteria provided	clinical testing