2-47475126-C-T
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.Arg621*) 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 (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000251.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 33
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:5
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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) -
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Lynch syndrome 1 Pathogenic:4
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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Hereditary cancer-predisposing syndrome Pathogenic:3
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. -
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. -
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Inherited MMR deficiency (Lynch syndrome) Pathogenic:1
PVS1,PM2,PP4_Strong -
Hereditary nonpolyposis colon cancer Pathogenic:1
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
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Lynch syndrome Pathogenic:1
Coding sequence variation introducing premature termination codon -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
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). 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: 90804). For these reasons, this variant has been classified as Pathogenic. -
Breast carcinoma Pathogenic:1
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Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at