chr2-47475100-C-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000251.3(MSH2):c.1835C>G(p.Ser612*) variant causes a stop gained change involving the alteration of a conserved nucleotide. 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:2
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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 (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: 25525159, 17192056, 15849733, 19419416, 26053027, 16636019, 31830689) -
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.S612* pathogenic mutation (also known as c.1835C>G), located in coding exon 12 of the MSH2 gene, results from a C to G substitution at nucleotide position 1835. This changes the amino acid from a serine to a stop codon within coding exon 12. This mutation has been reported in several hereditary non-polyposis colon cancer (HNPCC)/Lynch syndrome cohorts (Mangold E et al. Int. J. Cancer. 2005 Sep;116:692-702; Niessen RC et al. Gut. 2006 Dec;55:1781-8; Kamiza AB et al. PLoS ONE. 2015 Jun;10:e0130018). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 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. 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. -
Carcinoma of colon Pathogenic:1
The MSH2 p.Ser612X variant was identified in 3 of 4004 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Mangold 2005, Nielsen 2006). The variant was also identified in dbSNP (ID: rs63750493) as “With Pathogenic allele”, Clinvitae and ClinVar database (classified as pathogenic by InSight and Mayo Clinic), COSMIC, “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database (as Pathogenic), and UMD (2x with a causal classification). The variant was not identified in the 1000 Genomes Project, the NHLBI Exome Sequencing Project, the Exome Aggregation Consortium, the genome Aggregation Database (beta), “MMR Gene Unclassified Variants Database”, Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The p.Ser612X variant leads to a premature stop codon at position 612, 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. -
Lynch syndrome 1 Pathogenic:1
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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.Ser612*) 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: 15849733, 16636019, 26053027). ClinVar contains an entry for this variant (Variation ID: 90799). 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