rs63749811
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000251.3(MSH2):c.2113delG(p.Val705TrpfsTer5) 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 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:3
This frameshift variant alters the translational reading frame of the MSH2 mRNA and causes the premature termination of MSH2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with hereditary nonpolyposis colorectal cancer (HNPCC) (PMID: 8723682 (2996), 8872463 (1996), 10080150 (1999), 15342696 (2004), 16237223 (2005), 20052760 (2010)). It has also been reported in individuals with Lynch Syndrome (PMID: 18566915 (2009), 29238914 (2018)). Based on the available information, this variant is classified as pathogenic. -
PP4, PM2, PVS1 -
Frameshift 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 individuals with a personal or family history consistent with pathogenic variants in this gene, and segregates with disease in many affected individuals (Jeon et al. 1996; Moslein et al., 1996; Lin et al., 1999; Domingo et al., 2004; Hegde et al., 2005; Nilbert et al., 2009; Coolbaugh-Murphy et al., 2010); 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: 20052760, 15342696, 29238914, 16237223, 10080150, 8872463, 18566915, 8723682, 30787465) -
Hereditary cancer-predisposing syndrome Pathogenic:3
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The c.2113delG pathogenic mutation, located in coding exon 13 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 2113, causing a translational frameshift with a predicted alternate stop codon (p.V705Wfs*5). This mutation has been detected in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several with family histories meeting Amsterdam criteria (Jeon HM et al. Hum. Mutat., 1996;7:327-33; Moslein G et al. Hum Mol Genet, 1996 Sep;5:1245-52)(Lin X et al. Dig. Dis. Sci., 1999 Mar;44:553-9; Domingo E et al. J Med Genet, 2004 Sep;41:664-8; Nilbert M et al. Fam Cancer, 2009 Jun;8:75-83; Coolbaugh-Murphy MI et al. Hum Mutat, 2010 Mar;31:317-24; Cloyd JM et al. J Gastrointest Cancer, 2018 Mar;49:93-96). 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. -
This variant deletes 1 nucleotide in exon 13 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals and families affected with Lynch syndrome (PMID: 8723682, 8872463, 10080150, 18566915, 20052760, 29238914). 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. -
Lynch syndrome 1 Pathogenic:2
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: MSH2 c.2113delG (p.Val705TrpfsX5) 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 251476 control chromosomes. c.2113delG has been reported in the literature in multiple individuals affected with Lynch Syndrome (Moslein_1996, Lin_1999, Hegde_2005, Nilbert_2009, Coolbaugh-Murphy_2010). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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 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.Val705Trpfs*5) 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 Lynch syndrome-related cancers (PMID: 8723682, 8872463, 18566915, 20052760). It has also been observed to segregate with disease in related individuals. 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: 1760). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at