rs563410947
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000251.3(MSH2):c.803C>A(p.Ser268Ter) variant causes a stop gained change. 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. S268S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 29)
Consequence
MSH2
NM_000251.3 stop_gained
NM_000251.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.81
Genes affected
MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-47414279-C-A is Pathogenic according to our data. Variant chr2-47414279-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 973386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47414279-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.803C>A | p.Ser268Ter | stop_gained | 5/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.803C>A | p.Ser268Ter | stop_gained | 5/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 29
GnomAD3 genomes
?
Cov.:
29
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 29
GnomAD4 genome
?
Cov.:
29
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Lynch syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 28, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Lynch-like syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Constitutional Genetics Lab, Leon Berard Cancer Center | Jul 01, 2019 | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 13, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 973386). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 27064304, 33191490). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser268*) 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 | Apr 16, 2019 | The p.S268* pathogenic mutation (also known as c.803C>A), located in coding exon 5 of the MSH2 gene, results from a C to A substitution at nucleotide position 803. This changes the amino acid from a serine to a stop codon within coding exon 5. This alteration has been reported in a cohort of Australian patients with HNPCC (Sjursen W et al. Mol Genet Genomic Med, 2016 Mar;4:223-31) and in a woman with Muir-Torre syndrome (Smith J et al. Ann Diagn Pathol, 2012 Dec;16:485-8). 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at