Submissions for variant NM_000251.3(MSH2):c.942+3A>T

gnomAD frequency: 0.00072  dbSNP: rs193922376

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030256	SCV000107794	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99. Variant causes in-frame splicing aberration which interrupts know functional domains
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731319	SCV000052923	pathogenic	Hereditary nonpolyposis colon cancer	2021-09-08	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.942+3A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5 prime splicing donor site; two predict the variant weakens a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Liu_1994). The variant allele was found at a frequency of 3.3e-05 in 30582 control chromosomes. c.942+3A>T has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Liu_1994, Thibodeau_1996, Chan_1999, Desai_2000, Green_2002, Win_2011). These data indicate that the variant is very likely to be associated with disease. Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000201997	SCV000110277	pathogenic	not provided	2013-07-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000201997	SCV000149458	pathogenic	not provided	2020-04-13	criteria provided, single submitter	clinical testing	Originally reported to be a pathogenic founder variant in Newfoundland, but has since been hypothesized to be a mutational hotspot identified in individuals of varying ethnicities without a common haplotype identified (Desai 2000); Published functional studies demonstrate a damaging effect: skipping of exon 5 (Liu 1994, Auclair 2006); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Liu 1994, Froggatt 1999, Kurzawski 2005, Buchanan 2014, Rosty 2014, Harper 2016, Roth 2016, Ziada-Bouchaar 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 18270343, 10978353, 21598002, 8062247, 27064304, 26873718, 31857677, 25525159, 30702970, 29575718, 29665779, 30680046, 22883484, 25117503, 24323032, 23329266, 21642682, 23255516, 12362047, 19125127, 24603434, 19575290, 18809606, 25479140, 25345868, 10051005, 25648859, 25980754, 21056691, 22775459, 25110875, 20587412, 16395668, 22949379, 21636617, 27013479, 21681552, 26666765, 27468915, 26143115, 27601186, 27978560, 27357288, 27720647, 28243543, 19606495, 18566915, 28152038, 27713421, 28502729, 28514183, 26681312, 28873162, 28577310, 28874130, 29967423, 30093976, 31054147, 30553995, 25795746, 18460031, 31444830, 25025451, 32658311, 31615790, 33484353, 34178123, 31332305, 30875412, 30787465, 33726816)
Ambry Genetics	RCV000115549	SCV000185219	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	clinical testing	The c.942+3A>T intronic pathogenic mutation results from an A to T substitution 3 nucleotides after coding exon 5 in the MSH2 gene. In one study, this mutation was found in eight unrelated Lynch syndrome families. Six of the eight families (75%) had one family member diagnosed with either a keratocanthoma or sebaceous adenoma associated with Muir-Torre syndrome, along with some combination of colon, uterine, and/or ureter transitional cell cancers in the family (South CD et al. J. Natl. Cancer Inst. 2008 Feb;100:277-81). This mutation was also reported in a German patient diagnosed with malignant fibrous histiocytoma (MFH) (Brieger A et al. Fam. Cancer. 2011 Sep;10:591-5). Authors of one study claim that this is the most common recurrent de novo germline mutation in a human mismatch repair gene, accounting for approximately 11% of all known pathogenic MSH2 gene mutations (Desai DC et al. J. Med. Genet. 2000 Sep;37:646-52). Multiple studies have demonstrated that this mutation results in an mRNA transcript lacking coding exon 5 (Casey G et al. JAMA. 2005 Feb;293:799-809; Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54; Arnold S et al. Hum. Mutat. 2009 May;30:757-70; Chong G et al. Hum. Mutat. 2009 Aug;30:E797-812). Of note, this mutation is also designated as IVS5+3A>T in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000524424	SCV000211911	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 8062247, 10978353, 15222003, 19419416, 20682701, 21681552, 22883484, 24310308). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36580). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 5, but is expected to preserve the integrity of the reading-frame (PMID: 8062247, 16395668; Invitae). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000201997	SCV000257198	pathogenic	not provided	2023-01-30	criteria provided, single submitter	clinical testing	PP4, PP5, PM2, PS3, PS4_moderate
Counsyl	RCV000001844	SCV000487770	pathogenic	Lynch syndrome 1	2015-11-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000201997	SCV000601495	pathogenic	not provided	2023-07-12	criteria provided, single submitter	clinical testing	The MSH2 c.942+3A>T variant has been reported in the published literature in several affected individuals with Lynch Syndrome-related cancers (PMIDs: 23329266 (2013), 22949379 (2013), 24323032 (2014), 25117503 (2014), 28874130 (2017), 35734982 (2022), and 36421850 (2022)). A functional study demonstrated that this variant alters normal splicing and results in exon 5 skipping (PMID: 16395668 (2006)). It has also been described as the most common recurrent de novo germline variant in a human mismatch repair gene (PMID: 10978353 (2000)), as well as the most common Lynch Syndrome variant in the world (PMIDs: 20682701 (2010)). The frequency of this variant in the general population, 0.000033 (1/30582 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper MSH2 mRNA splicing. Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000115549	SCV000690146	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	This variant causes an A to T nucleotide substitution at the +3 position of intron 5 of the MSH2 gene. RNA studies have shown this variant caused skipping of exon 5 (r.793_942del) and in-frame deletion of 50 amino acids in the DNA binding domain (PMID: 8062247, 16395668, 19267393). This variant has been reported as a recurrent de novo mutation in individuals affected with Lynch syndrome-associated cancer in different ethnicities (PMID: 10978353). This variant has been reported in many individuals and families with Lynch syndrome or suspected Lynch syndrome worldwide (PMID: 8062247, 10413423, 10446963, 11920650, 12112654, 12362047, 15222003, 16203774, 16395668, 17312306, 18625694, 19130300, 19419416, 20682701, 21681552, 22883484), and shown to segregate with Lynch syndrome cancers in family studies (PMID: 19267393). This variant is considered to be a founder mutation in the Newfoundland population (PMID: 20682701). This variant has been identified in 1/30582 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000030256	SCV000711430	pathogenic	Lynch syndrome	2016-03-18	criteria provided, single submitter	clinical testing	The c.942+3A>T variant in MSH2 has been reported in >150 individuals with Lynch syndrome and is considered a founder variant in the Newfoundland population (Lab Corp database, Woods 2010). Data from large population studies is insufficient t o assess the frequency of this variant. In vitro functional studies provide some evidence that the c.942+3A>T variant impacts splicing (Auclair 2006). In additi on, it has been classified as Pathogenic on December 18, 2013 by the ClinGen-app roved InSiGHT expert panel (ClinVar SCV000107794.2). In summary, this variant me ets our criteria to be classified as pathogenic for Lynch syndrome in an autosom al dominant manner based upon the on the predicted impact to the protein.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000001844	SCV000743207	pathogenic	Lynch syndrome 1	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000001844	SCV000744270	pathogenic	Lynch syndrome 1	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000201997	SCV000806051	pathogenic	not provided	2017-06-27	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000030256	SCV000914299	pathogenic	Lynch syndrome	2019-01-30	criteria provided, single submitter	research
Institute of Human Genetics, University of Leipzig Medical Center	RCV000001844	SCV001428898	pathogenic	Lynch syndrome 1	2018-04-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000201997	SCV002017564	pathogenic	not provided	2023-01-04	criteria provided, single submitter	clinical testing
Laboratory of Molecular and Cellular Biology, University of Science and Technology Houari Boumediene	RCV000001844	SCV002318379	pathogenic	Lynch syndrome 1		criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115549	SCV002526774	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-10	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000001844	SCV004018422	pathogenic	Lynch syndrome 1	2023-03-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8062247].
CeGaT Center for Human Genetics Tuebingen	RCV000201997	SCV004033723	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	MSH2: PS3, PS4, PM2, PP1
Baylor Genetics	RCV000001844	SCV004196207	pathogenic	Lynch syndrome 1	2023-10-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000201997	SCV004562878	pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing	The MSH2 c.942+3A>T variant (rs193922376) is well-described in the literature to be associated with Lynch syndrome and colorectal cancer (Desai 2000, Lage 2004, Liu 1994, Woods 2010, Mismatch Repair Genes Variant Database and references therein). This variant is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 36580). This is an intronic variant in a moderately conserved nucleotide, and RNA analyses indicate this variant weakens the canonical donor splice site of intron 5 and leads to exon 5 skipping (Auclair 2006, Liu 1994). Based on available information, this variant is considered to be pathogenic. References: Link to Mismatch Repair Genes Variant Database: http://www.med.mun.ca/mmrvariants/search_results.aspx Auclair J et al. Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. Hum Mutat. 2006 Feb;27(2):145-54. PMID: 16395668. Desai DC et al. Recurrent germline mutation in MSH2 arises frequently de novo. J Med Genet. 2000 Sep;37(9):646-52. PMID: 10978353. Lage PA et al. Association of colonic and endometrial carcinomas in Portuguese families with hereditary nonpolyposis colorectal carcinoma significantly increases the probability of detecting a pathogenic mutation in mismatch repair genes, primarily the MSH2 gene. Cancer. 2004 Jul 1;101(1):172-7. PMID: 15222003. Liu B et al. hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res. 1994 Sep 1;54(17):4590-4. PMID: 8062247. Woods MO et al. The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease. Gut. 2010 Oct;59(10):1369-77. PMID: 20682701.
OMIM	RCV000001844	SCV000021989	pathogenic	Lynch syndrome 1	2000-09-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353565	SCV000592480	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 c.942+3A>T variant was identified in 12 of 2642 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer, and was not identified in 200 control chromosomes from healthy individuals (Auclair 2006, Brieger 2011, Canard 2012, Froggatt 1996, Grindedal 2009, Kurzawski 2002, Sheng 2008). The variant was also identified by our laboratory in 8 individuals with colorectal cancer. The variant was identified in dbSNP (ID: rs193922376) as “With Pathogenic allele”, Clinvitae database (as pathogenic), “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), ClinVar database (classified as pathogenic by InSight, Emory Genetics, Ambry genetics, Invitae, LabCorp, COGR, Mayo Clinic, GeneDx, OMIM) and UMD (111X with a “causal” classification). The c.942+3A>T variant is located at the donor splice site (or 3’ splice site of exon 5) but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. Furthermore, several population studies suggest the variant lead to an in-frame deletion of exon 5 and loss of MSH2 protein expression (Auclair 2006, Brieger 2011, Canard 2012, Kurzawski 2002). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249912	SCV001423929	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001579303	SCV001805837	pathogenic	Breast carcinoma	2021-08-21	no assertion criteria provided	clinical testing
GeneReviews	RCV000001844	SCV002054065	not provided	Lynch syndrome 1		no assertion provided	literature only