Submissions for variant NM_000251.3(MSH2):c.1730T>C (p.Ile577Thr)

gnomAD frequency: 0.00018  dbSNP: rs63749910

Total submissions: 23

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	RCV000034552	SCV000149417	likely benign	not provided	2020-07-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27958275, 22703879, 16636019, 19117025, 22006311, 16736289, 16885385, 21056691, 25871441, 16408224, 26878173, 26182300)
Ambry Genetics	RCV000115508	SCV000186134	likely benign	Hereditary cancer-predisposing syndrome	2018-09-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000524356	SCV000254392	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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	RCV000034552	SCV000601437	uncertain significance	not provided	2020-09-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212607	SCV000696225	benign	not specified	2021-03-07	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 Hereditary Nonpolyposis Colorectal Cancer (0.00015 vs 0.00057), allowing no conclusion about variant significance. 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). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the literature and also observed at our laboratory ( MUTYH c.36+1G>A, Niessen_2006; BRCA1 c.3005delA , p.Asn1002fsX22 at our laboratory), providing supporting evidence for a benign role. A study that computed a tumor characteristic likelihood ratio (TCLR) in combination with in-silico predictors and multifactorial variant prediction (MVP) model including allele frequency, co-occurrence, co-segregation, clinical and family history information classified this variant a benign (Li_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV003323281	SCV000837837	benign	Hereditary nonpolyposis colon cancer	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115508	SCV000910631	likely benign	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000415673	SCV001299642	uncertain significance	Lynch syndrome 1	2019-05-16	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798064	SCV002042097	uncertain significance	Breast and/or ovarian cancer	2021-03-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212607	SCV002070921	uncertain significance	not specified	2019-12-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1730T>C, in exon 11 that results in an amino acid change, p.Ile577Thr. This sequence change has been described previously in individuals with colorectal cancer, ovarian cancer or adenocarcinoma of the endometrium (PMID: 21056691, PMID: 19117025, PMID: 16885385, PMID: 16736289). It has been described in the gnomAD database with a low population frequency of 0.029% in non-Finnish European subpopulation (dbSNP rs63749910). The p.Ile577Thr change affects a moderately conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Ile577Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these evidences and the lack of functional studies, the clinical significance of the p.Ile577Thr change remains unknown at this time.
Sema4, Sema4	RCV000115508	SCV002534400	likely benign	Hereditary cancer-predisposing syndrome	2021-06-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212607	SCV002552239	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034552	SCV003799242	likely benign	not provided	2023-10-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944880	SCV004764141	likely benign	MSH2-related condition	2021-05-12	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415673	SCV000493755	uncertain significance	Lynch syndrome 1	2016-03-30	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000034552	SCV001549565	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH2 p.Ile577Thr variant was identified in 6 of 1950 proband chromosomes (frequency: 0.003) from individuals or families with endometrial, colorectal, and ovarian cancer (Hampel 2006, Limburg 2011, South 2009, Spaepen 2006, Walsh 2011), and was present in 1 of 1142 control chromosomes (frequency: 0.0009) from healthy individuals (Johnston 2012). The variant was also identified in dbSNP (ID: rs63749910) as “With Uncertain significance allele”, ClinVar (as likely benign, reviewed by expert panel and Ambry Genetics, and as uncertain significance by GeneDx, Invitae, Knight Diagnostics, Laboratory for Molecular Medicine, Quest Diagnostics, Integrated Genetics, and Biesecker Lab), Clinvitae (6x), UMD-LSDB (1x as uncertain significance), Insight Colon Cancer Gene Variant Database (5x as "class 2 likely not pathogenic"), and Mismatch Repair Genes Variant Database (1x). The variant was not identified in COGR, Cosmic, MutDB, or Zhejiang University Database. The variant was identified in control databases in 41 of 276890 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24008 chromosomes (freq: 0.00008), Other in 1 of 6458 chromosomes (freq: 0.0002), Latino in 1 of 34416 chromosomes (freq: 0.00003), and European (Non-Finnish) in 37 of 126452 chromosomes (freq: 0.0003); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. One study reported the variant was found to co-occur with a pathogenic MUTYH variant: c.36+1G>A (Niessen 2006). The p.Ile577 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000034552	SCV001744701	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000034552	SCV001905886	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000034552	SCV001921467	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000034552	SCV002037398	likely benign	not provided		no assertion criteria provided	clinical testing