chr2-47476402-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.2041C>T(p.Gln681Ter) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Q681Q) has been classified as Likely benign. 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.2041C>T | p.Gln681Ter | stop_gained | 13/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.2041C>T | p.Gln681Ter | stop_gained | 13/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Lynch syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 07, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Lynch syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 12, 2016 | Variant summary: The MSH2 c.2041C>T (p.Gln681X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2113delG, p.Val705fsX5; c.2152C>T, p.Gln718X; c.2633_2634delAG, p.Glu878fsX3). One in silico tool predicts a damaging outcome for this variant. The variant has been reported in affected individuals in the literature and is absent in 121330 control chromosomes. Taken together, this variant is classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2017 | This variant is denoted MSH2 c.2041C>T at the cDNA level and p.Gln681Ter (Q681X) at the proteinlevel. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA),and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNAdecay. This variant has been reported at least one family meeting modified Amsterdam criteria for Lynch syndrome(Parc 2003) and is considered pathogenic - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 23, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 428498). This premature translational stop signal has been observed in individual(s) with hereditary non-polyposis colorectal cancer (PMID: 12624141, 24710284). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln681*) 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). - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 13, 2021 | The p.Q681* pathogenic mutation (also known as c.2041C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2041. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This alteration has been reported in a French cohort of patients suspected of having HPNCC/Lynch syndrome (Parc Y et al. J. Med. Genet. 2003 Mar;40:208-13). This variant has also been identified in a family meeting Amsterdam criteria (Liu Y et al. PLoSOne. 2014 Apr 7;9(4):e94170). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at