2-47475126-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.1861C>T(p.Arg621Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R621R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
MSH2
NM_000251.3 stop_gained
NM_000251.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 4.15
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]
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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 2-47475126-C-T is Pathogenic according to our data. Variant chr2-47475126-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 90804.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475126-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.1861C>T | p.Arg621Ter | stop_gained | 12/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.1861C>T | p.Arg621Ter | stop_gained | 12/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:18
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 22, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 01, 2020 | 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 Not observed in large population cohorts (Lek et al., 2016) Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Maliaka 1996, Parc 2003, Zavodna 2006, Overbeek 2007, Papp 2007, van Puijenbroek 2008, Bonadona 2011, Brieger 2011, Everett 2014, Kury 2014, Vierkoetter 2014, Goodfellow 2015, Sunga 2017, Jiang 2019, Rashid 2019) This variant is associated with the following publications: (PMID: 31615790, 32658311, 31660093, 30521064, 29489754, 28944238, 17453009, 28874130, 27863258, 25093288, 26552419, 16830052, 25504677, 23741719, 18415027, 24415873, 21642682, 21598002, 20007843, 18772310, 12624141, 28449805, 25525159, 25006859, 17569143, 8566964) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 29, 2019 | - - |
Lynch syndrome 1 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 04, 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 | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 06, 2022 | This variant changes 1 nucleotide in exon 12 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 reported in individuals affected with Lynch syndrome or suspected of having Lynch syndrome (PMID: 8566964, 12624141, 17569143, 18772310, 20007843, 21598002, 21642682, 27629256), or colorectal cancer (PMID: 24415873, 26552419, 29967336). 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 | curation | Sema4, Sema4 | Feb 06, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 21, 2021 | The p.R621* pathogenic mutation (also known as c.1861C>T), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1861. This changes the amino acid from an arginine to a stop codon within coding exon 12. This mutation has been reported in multiple HNPCC/Lynch syndrome families; several who meet Amsterdam criteria and/or have tumors that demonstrated loss of MSH2 and MSH6 by IHC (Maliaka YK et al. Hum. Genet. 1996 Feb;97(2):251-5; Weber TK et al. Cancer Res. 1997 Sep;57(17):3798-803; Niessen RC et al. Gut 2006 Dec;55(12):1781-8; Overbeek LIH et al. Br. J. Cancer. 2007 May;96(10):1605-1612; Papp J et al. World J. Gastroenterol. 2007 May;13(19):2727-32; Vierkoetter KR et al. Gynecol Oncol, 2014 Oct;135:81-4; Kang SY et al. Int J Cancer, 2015 Apr;136:1568-78; Dominguez-Valentin M et al. Front Oncol, 2016 Aug;6:189; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Rashid MU et al. Hered Cancer Clin Pract, 2019 Oct;17:29; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Yanus GA et al. Eur J Med Genet, 2020 Mar;63:103753; Akcay IM et al. Int J Cancer, 2021 01;148:285-295). 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. - |
Hereditary nonpolyposis colon cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 04, 2021 | Variant summary: MSH2 c.1861C>T (p.Arg621X) 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 251474 control chromosomes. c.1861C>T has been reported in the literature in multiple individuals affected with MSH2-associated cancers (Maliaka_1996, Papp_2007, Bonadona_2011, Vierkoetter_2014, Kang_2015, Dominguez-Valentin_2016). These data indicate that the variant is very likely to be associated with disease. Seven 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
Pathogenic, no assertion criteria provided | clinical testing | Constitutional Genetics Lab, Leon Berard Cancer Center | Jul 01, 2019 | - - |
Lynch syndrome Pathogenic:1
Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Coding sequence variation introducing premature termination codon - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change creates a premature translational stop signal (p.Arg621*) 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 and colorectal cancer (PMID: 8566964, 12624141, 17569143, 18772310, 20007843, 21598002, 21642682, 24415873). ClinVar contains an entry for this variant (Variation ID: 90804). For these reasons, this variant has been classified as Pathogenic. - |
Breast carcinoma Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Sep 12, 2021 | - - |
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
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
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