2-47414421-A-T
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong
The NM_000251.3(MSH2):c.942+3A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_000251.3 splice_region, intron
Scores
Clinical Significance
Conservation
Publications
- Lynch syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
- Lynch syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
- Muir-Torre syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
- mismatch repair cancer syndrome 1Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- mismatch repair cancer syndrome 2Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
- ovarian cancerInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- malignant pancreatic neoplasmInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- prostate cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- rhabdomyosarcomaInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
- breast cancerInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
- hereditary breast carcinomaInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MSH2 | NM_000251.3 | c.942+3A>T | splice_region_variant, intron_variant | Intron 5 of 15 | ENST00000233146.7 | NP_000242.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MSH2 | ENST00000233146.7 | c.942+3A>T | splice_region_variant, intron_variant | Intron 5 of 15 | 1 | NM_000251.3 | ENSP00000233146.2 |
Frequencies
GnomAD3 genomes 0.000699 AC: 2AN: 2862Hom.: 0 Cov.: 0 show subpopulations
GnomAD2 exomes AF: 0.0000327 AC: 1AN: 30582 AF XY: 0.0000630 show subpopulations
GnomAD4 exome AF: 0.00333 AC: 29AN: 8714Hom.: 0 Cov.: 0 AF XY: 0.00392 AC XY: 17AN XY: 4334 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
Age Distribution
GnomAD4 genome 0.000697 AC: 2AN: 2868Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 1496 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Lynch syndrome 1 Pathogenic:8Uncertain:1Other:1
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This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8062247]. -
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
not provided Pathogenic:9
PP4, PP5, PM2, PS3, PS4_moderate -
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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) -
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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. -
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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. -
MSH2: PS3, PS4, PM2, PP1 -
Lynch syndrome Pathogenic:4
Multifactorial likelihood analysis posterior probability >0.99. Variant causes in-frame splicing aberration which interrupts know functional domains -
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. -
The c.942+3A>T variant in MSH2 has been reported in >150 individuals with Lynch syndrome (LabCorp database, Woods 2010). This variant has been identified in 1/12862 of European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). In vitro functional studies show that the c.942+3A>T variant leads to an in-frame deletion of exon 5 (Auclair 2006). In addition, it has been classified as Pathogenic on December 18, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107794.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon the predicted impact to the protein, low frequency in controls and presence in affected individuals. ACMG/AMP Criteria applied: PS4, PM2, PS3_Supporting, PVS1_Strong. -
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Hereditary cancer-predisposing syndrome Pathogenic:3
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. -
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. -
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MSH2-related disorder Pathogenic:1
The MSH2 c.942+3A>T variant is predicted to interfere with splicing. This variant is a documented causative variant (germline and somatic) for several types of cancers (e.g. cancers of bladder, colorectal, ovarian, sebaceous gland, prostate etc.) (Haraldsdottir et al. 2014. PubMed ID: 25194673; Susswein et al. 2016, Table S1, PubMed ID: 26681312; Dominguez-Valentin et al. 2016, PubMed ID: 27013479). Also, it is a recurrent pathogenic variant of nonpolyposis colorectal cancer (Desai et al. 2000, PubMed ID: 10978353) and reported as both a de novo and a familial variant and represents above 10% of all MSH2 positive cases (Mangold et al. 2005, PubMed ID: 15849733). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/36580). This variant is interpreted as pathogenic. -
Carcinoma of colon Pathogenic:1
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. -
Hereditary nonpolyposis colon cancer Pathogenic:1
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. -
Lynch-like syndrome Pathogenic:1
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Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
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. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. 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; internal data). For these reasons, this variant has been classified as Pathogenic. -
Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 Pathogenic:1
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Breast carcinoma Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at