2-47429812-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000251.3(MSH2):c.1147C>T(p.Arg383Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
MSH2
NM_000251.3 stop_gained
NM_000251.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.30
Genes affected
MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-47429812-C-T is Pathogenic according to our data. Variant chr2-47429812-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 90554.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47429812-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MSH2 | NM_000251.3 | c.1147C>T | p.Arg383Ter | stop_gained | 7/16 | ENST00000233146.7 | NP_000242.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MSH2 | ENST00000233146.7 | c.1147C>T | p.Arg383Ter | stop_gained | 7/16 | 1 | NM_000251.3 | ENSP00000233146 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461826Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727218
GnomAD4 exome
AF:
AC:
2
AN:
1461826
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
727218
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:22Uncertain:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:8Uncertain:1
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | MSH2: PVS1, PM2, PS4:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 10, 2017 | The MSH2 c.1147C>T, p.Arg383Ter variant (rs63749849) is a recurrent alteration in families with hereditary nonpolyposis colorectal cancer (Buerstedde 1995, Heiniman 2000, Lamberti 1999, Lin 1999, Mangold 2005, Mangold 2005b, Mueller-Koch 2005, Overbeek 2007, Pistorius 2000, Spaepen 2006, Terdiman 2001). It is classified as pathogenic in ClinVar by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (Variation ID: 90554). The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References Buerstedde J et al. Detection of new mutations in six out of 10 Swiss HNPCC families by genomic sequencing of the hMSH2 and hMLH1 genes. J Med Genet. 1995; 32(11):909-12. Heinimann K et al. Influence of selection criteria on mutation detection in patients with hereditary nonpolyposis colorectal cancer. Cancer. 1999; 85(12):2512-8. Lamberti C et al. Microsatellite instability-a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer. Gut. 1999; 44(6):839-43. Lin X et al. Reduction in hMSH2 mRNA levels by premature translation termination: implications for mutation screening in hereditary nonpolyposis colorectal cancer. Dig Dis Sci. 1999; 44(3):553-9. Mangold E et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2005; 116(5):692-702. Mangold E et al. Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining. J Pathol. 2005b; 207(4):385-95. Mueller-Koch Y et al. Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut. 2005; 54(12):1733-40. Overbeek L et al. Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer. Br J Cancer. 2007 May 21;96(10):1605-12. Epub 2007 Apr 24. Pistorius S et al. Clinical consequences of molecular diagnosis in families with mismatch repair gene germline mutations. Int J Colorectal Dis. 2000; 15(5-6):255-63. Spaepen M et al. Germline mutations of the hMLH1 and hMSH2 mismatch repair genes in Belgian hereditary nonpolyposis colon cancer (HNPCC) patients. Fam Cancer. 2006; 5(2):179-89. Terdiman J et al. Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing. Gastroenterology. 2001; 120(1):21-30. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 22, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jun 17, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 02, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Identified in individuals with personal and/or family histories consistent with Lynch syndrome (Buerstedde et al., 1995; Corleto et al., 2005; Jasperson et al., 2010; Rosty et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 24851142, 11093816, 11151427, 19731080, 24344984, 15872200, 31830689, 28888541, 25525159, 16437731, 25117503, 8592341, 21642682, 25194673, 25430799, 23990280, 23741719, 10375096, 22034109, 18270343, 10080150, 16736289, 10323887, 11179758, 11208710, 15955785, 17453009, 16996571, 27601186, 28502729, 28874130, 30521064, 31054147, 31615790, 33372952, 33484353, 30787465, 35264596, 31332305) - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 04, 2018 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Lynch syndrome 1 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 23, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Sep 17, 2023 | This sequence change creates a premature translational stop signal (p.Arg383*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with prostate cancer, breast , ovarian cancer and multiple HNPCC/Lynch syndrome families, and several had tumors demonstrating microsatellite instability and/or absence of MSH2 protein on immunohistochemistry (PMID: 24851142, 11093816, 11151427, 19731080, 24344984, 15872200, 31830689, 28888541, 25525159, 16437731, 25117503, 8592341, 21642682, 25194673, 25430799, 23990280, 23741719, 10375096, 22034109, 18270343, 10080150, 16736289, 10323887, 11179758, 11208710, 15955785, 17453009, 16996571, 27601186, 28502729, 28874130, 30521064, 31054147, 31615790, 33372952, 33484353, 30787465, 35264596, 31332305). ClinVar contains an entry for this variant (Variation ID: 90554) classified as pathogenic . For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 28, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jul 07, 2022 | The Arg383* variant has been identified in numerous patients with Lynch syndrome and a function study has shown that the variant results in loss of the allele through nonsense mediated decay. The variant is absent from the GnomAD population database and is listed as a class 5 (pathogenic) variant in InSiGHT. The clinical features and IHC results of this case are highly specific for variants in the MSH2 gene. Variant not detected in blood. - |
Lynch syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Coding sequence variation introducing a premature termination codon - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 17, 2021 | This variant changes 1 nucleotide in exon 7 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in over 15 individuals and families affected with Lynch syndrome and associated cancers (PMID: 8592341, 10080150, 10323887, 11151427, 15872200, 16736289, 16996571, 19731080, 21642682, 24344984, 23990280, 25117503) and in three individuals and families affected with breast and ovarian cancer (PMID: 22034109, 24549055). This variant has been reported to segregate with disease in multiple families (combined segregation likelihood ratio for pathogenicity of 150.3:1; InSiGHT database). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 02, 2021 | The p.R383* pathogenic mutation (also known as c.1147C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide position 1147. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation has been detected in multiple HNPCC/Lynch syndrome families, and several had tumors demonstrating microsatellite instability and/or absence of MSH2 protein on immunohistochemistry (Buerstedde JM et al. J. Med. Genet., 1995 Nov;32:909-12; Heinimann K et al. Cancer, 1999 Jun;85:2512-8; Lamberti C et al. Gut, 1999 Jun;44:839-43; Lin X et al. Dig. Dis. Sci., 1999 Mar;44:553-9; Pistorius SR et al. Int J Colorectal Dis, 2000 Nov;15:255-63; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Hampel H et al. N Engl J Med, 2005 May;352:1851-60; Mangold E et al. J Pathol, 2005 Dec;207:385-95; Spaepen M et al. Fam Cancer, 2006;5:179-89; South CD et al. J. Natl. Cancer Inst., 2008 Feb;100:277-81; Jasperson KW et al. Fam Cancer, 2010 Jun;9:99-107; Bonadona V et al. JAMA, 2011 Jun;305:2304-10; Buerki N et al. Genes Chromosomes Cancer, 2012 Jan;51:83-91; Dominguez-Valentin M et al. Hered Cancer Clin Pract, 2013 Dec;11:18; Rosty C et al. Fam. Cancer, 2014 Dec;13:573-82; Tzortzatos G et al. Hered Cancer Clin Pract, 2014;12:14; Goldberg Y et al. Fam Cancer, 2014 Mar;13:65-73; Xiong HY et al. Science, 2015 Jan;347:1254806; Goldberg Y et al. Clin Genet, 2015 Jun;87:549-53; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Tian W et al. Int J Cancer, 2019 09;145:1290-1298; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199; Vietri MT et al. Med Oncol, 2021 Jan;38:13). This mutation has also been identified in a cohort of high-risk breast/ovarian cancer patients (Castéra L et al. Eur J Hum Genet, 2014 Nov;22:1305-13). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
MSH2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 31, 2024 | The MSH2 c.1147C>T variant is predicted to result in premature protein termination (p.Arg383*). This nonsense variant has been previously reported in several individuals with a personal or family history of Lynch syndrome and various cancers including urinary tract cancer, colorectal cancer, prostate cancer, and breast cancer (Wischhusen et al. 2020. PubMed ID: 31615790; Jiang et al. 2019. PubMed ID: 30521064; Rosty et al. 2014. PubMed ID: 25117503; Castera et al. 2014. PubMed ID: 24549055). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/90554/). Nonsense variants in MSH2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Hereditary nonpolyposis colon cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 13, 2021 | Variant summary: MSH2 c.1147C>T (p.Arg383X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251460 control chromosomes. c.1147C>T has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome and associated tumors (example, Rossi_2017, Bonadona_2011, Banville_2006, Mangold_2005, Buerstedde_1995). These data indicate that the variant is very likely to be associated with disease. Banville et al (2006) showed loss of expression of MSH2 and MSH6 in tumor samples from a patient carrying this variant. Thompson et al (2014) reported a truncated polypeptide of MSH2 following protein truncation testing performed on patient RNA. Multiple clinical diagnostic laboratories and an expert panel (InSiGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Lynch-like syndrome Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Constitutional Genetics Lab, Leon Berard Cancer Center | Jul 01, 2019 | - - |
Rhabdomyosarcoma Pathogenic:1
| Pathogenic, no assertion criteria provided | provider interpretation | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Sep 01, 2020 | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Arg383*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome, prostate cancer, and breast and/or ovarian cancer (PMID: 8592341, 15849733, 15872200, 23990280, 24344984, 24549055, 25117503, 25430799). ClinVar contains an entry for this variant (Variation ID: 90554). For these reasons, this variant has been classified as Pathogenic. - |
Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at