rs63750326
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000251.3(MSH2):c.811_814delTCTG(p.Ser271ArgfsTer2) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000251.3 frameshift
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 genome
ClinVar
Submissions by phenotype
Lynch syndrome 1 Pathogenic:4
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This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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Lynch syndrome Pathogenic:2
Coding sequence variation resulting in a stop codon -
Variant summary: The MSH2 c.811_814delTCTG (p.Ser271Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 121074 control chromosomes. Multiple publications have cited the variant in affected individuals and observed loss of MSH2 protein expression. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
not provided Pathogenic:2
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Classification criteria: PVS1, PM2_supporting, PP4_moderate -
not specified Pathogenic:1
The MSH2 c.811_814del; p.Ser271fs variant (also known as 808delGTCT) is reported in the medical literature in at least two individuals that fulfilled diagnostic criteria for HNPCC (Ewald 2007, Farrington 1998, Lagerstedt 2007, Liu 1995). The variant is described in the ClinVar database (Variation ID: 91222), in the dbSNP variant database (rs587779185), but is not listed in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The variant deletes four nucleotides, creates a frameshift and is predicted to result in a truncated protein or mRNA subject to non-sense mediated decay. Considering available information, this variant is classified as pathogenic. References Ewald J et al. Immunohistochemical staining for mismatch repair proteins, and its relevance in the diagnosis of hereditary non-polyposis colorectal cancer. Br J Surg. 2007 Aug;94(8):1020-7. Farrington SM et al. Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls. Am J Hum Genet. 1998 Sep;63(3):749-59. Lagerstedt Robinson K et al. Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. J Natl Cancer Inst. 2007 Feb 21;99(4):291-9. Liu B et al. Genetic instability occurs in the majority of young patients with colorectal cancer. Nat Med. 1995 Apr;1(4):348-52. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Ser271Argfs*2) 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-related cancers (PMID: 7585065, 9718327, 15235034, 17312306, 27601186). This variant is also known as 811del4 and 808_811delCTGT. ClinVar contains an entry for this variant (Variation ID: 91222). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.811_814delTCTG pathogenic mutation, located in coding exon 5 of the MSH2 gene, results from a deletion of 4 nucleotides between nucleotide positions 811 and 814, causing a translational frameshift with a predicted alternate stop codon (p.S271Rfs*2). This mutation has been detected in individuals meeting Amsterdam criteria and/or with Lynch syndrome tumors displaying microsatellite instability and loss of MSH2 protein expression (Liu B et al. Nat. Med. 1995 Apr;1(4):348-52; Roupret M et al. J. Med. Genet. 2004 Jul;41(7):e91; Lagerstedt Robinson et al. J. Natl. Cancer Inst. 2007 Feb;99(4):291-9; Ewald J et al. Br. J. Surg. 2007 Aug;94(8):1020-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as 811del4, 808_811delCTGT, and 808delGTCT in published literature. 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. -
Endometrial carcinoma Pathogenic:1
The MSH2 p.Ser271Argfs*2 variant was not identified in the literature nor was it identified in the dbSNP database. The variant was identified in ClinVar (classified as pathogenic by Invitae, Counyl, Ambry Genetics and two other submitters), and in UMD-LSDB (2x as causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.811_814del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 271 and leads to a premature stop codon at position 272. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in MSH2 associated cancers and 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. -
Computational scores
Source:
Splicing
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