2-47429881-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001406658.1(MSH2):c.-141C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,788 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 (★★★).
Frequency
Consequence
NM_001406658.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461788Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727198
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:9
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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; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 8261515, 10793088, 11879922, 15713769, 17312306, 18841495, 21239990, 24278394, 25420488, 28491141, 28577310, 27016151); Not observed 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: 10793088, 24278394, 11879922, 21239990, 15713769, 28577310, 28944238, 29025352, 31794323, 32782288, 20591884, 18841495, 17312306, 8261515, 27016151, 25420488, 26300997, 26850131, 15849733, 19760518, 28449805, 20223024, 24710284, 28874130, 29238914, 24969397, 28491141, 34178123, 31615790, 30787465) -
MSH2: PVS1, PM2, PS4:Moderate -
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Lynch syndrome 1 Pathogenic:7
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The MSH2 c.1216C>T variant is classified as Pathogenic (PVS1, PS4, PM2, PP4, PP5) The MSH2 c.1216C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 406 (PVS1). The variant has been frequently reported in probands with a clinical presentation of colorectal cancer (PS4). This variant is absent from population databases (PM2). The clinical features of this case are highly specific for the MSH2 gene due to loss of expression of MSH2/MSH in IHC tumour staining (PP4). The variant has been reported in dbSNP (rs63751108) and in the HGMD database: CM930497. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 1755), including the InSiGHT group (PP5). -
The pathogenic MSH2 family variant was detected in this specimen. This sequence change creates a premature translational stop signal (p.Arg406*) 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 (PMID: 10793088,24278394, 11879922, 21239990, 15713769, 28577310, 28944238, 29025352, 20591884, 18841495, 17312306, 8261515, 27016151, 25420488, 26300997, 26850131, 15849733, 19760518, 28449805, 20223024, 24710284, 28874130, 29238914, 24969397, 28491141, 31615790). ClinVar contains an entry for this variant (Variation ID: 1755). For these reasons, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic mutations in the MSH2 gene cause Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC), also known as Lynch Syndrome. -
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This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Lynch syndrome Pathogenic:3
The p.Arg406X variant in MSH2 has been reported in >15 individuals with MSH2-associated cancers and segregated with disease in at least 1 affected relative (Leach 1993, Liu 1994, Weber 1997, Dunlop 1997, Wahlberg 1999, Pistoriu 2000, Mangold 2005, Casey 2005, Kurzawski 2006, Spaepen 2006, Guillem 2007, Choi 2009, Grindedal 2009, van der Post 2010, and Ponti 2014). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 406, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH2 gene is an established disease mechanism in individuals with Lynch syndrome. In addition, this variant was classified as pathogenic on Sept 13, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107079.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon reports in literature and absence from controls. ACMG/AMP Criteria applied: PVS1; PS4; PM2. -
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Coding sequence variation introducing a premature termination codon -
Carcinoma of colon Pathogenic:2
The MSH2 p.Arg406X variant was identified in 8 of 2328 proband chromosomes (frequency: 0.003) from Polish, German, Belgian, Uruguayan, British and Canadian individuals or families with Lynch Syndrome (Sarroca 2005, Kurzawski 2006, Mangold 2005, Spaepen 2006, Taylor 2003, Choi 2009). The variant was also identified in dbSNP (ID: rs63751108) “With Pathogenic allele”, Clinvitae database (classification pathogenic), COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as pathogenic and reviewed by an expert panel, submitters: InSiGHT, Ambry Genetics, LabCorp, OMIM, and Mayo Clinic), and UMD (18x with a “causal” classification). The p.Arg406X variant leads to a premature stop codon at position 406, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:2
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 reported in multiple individuals affected with Lynch syndrome (PMID: 8261515, 12362047, 15713769, 15849733, 19459153, 20223024, 20591884, 21239990, 21590452, 24278394, 24278394, 24710284, 27016151, 30376427). 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.R406* pathogenic mutation (also known as c.1216C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide position 1216. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation has been detected in multiple families meeting Amsterdam criteria. Tumor samples from two of these affected exhibited loss of the MSH2 protein by IHC (De Lellis L et al. PLoS ONE. 2013 Nov;8(11):e81194; Chong G et al. Hum. Mutat. 2009 Aug;30(8):E797-812; Casey G et al. JAMA. 2005 Feb;293(7):799-809). One study detected this mutation in three HNPCC families and noted that it was not observed in 180 healthy control individuals (Pastrello C et al. Genet. In Med. 2011 Feb;13(2):115-24). This mutation was also seen in an individual affected with urinary bladder cancer at age 58 in addition to colorectal cancer at ages 33 and 34; authors suggested that MSH2 mutations may confer a higher risk of urinary tract cancer (van der Post RS et al. J. Med. Genet. 2010 Jul;47(7);464-70). This mutation has been reported in an individual with gallbladder cancer (Cloyd JM et al. Gastrointest Cancer. 2018 Mar;49(1):93-96) and in individuals with soft tissue sarcoma and sebaceous adenoma (Latham A et al. J Clin Oncol. 2018 Oct;JCO1800283). 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. -
Gastric cancer Pathogenic:1
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Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg406*) 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 (PMID: 8261515, 15713769, 20223024, 20591884, 24710284). 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: 1755). 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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at