chr2-47478336-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000251.3(MSH2):c.2275G>T(p.Gly759Ter) 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. G759G) 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.2275G>T | p.Gly759Ter | stop_gained | 14/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.2275G>T | p.Gly759Ter | stop_gained | 14/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Lynch syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 08, 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, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Coding sequence variation introducing premature termination codon - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 08, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90946). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and prostrate cancer (PMID: 15342696, 16034045, 19723918, 27601186, 28514183). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly759*) 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 | Mar 03, 2023 | The p.G759* pathogenic mutation (also known as c.2275G>T), located in coding exon 14 of the MSH2 gene, results from a G to T substitution at nucleotide position 2275. This changes the amino acid from a glycine to a stop codon within coding exon 14. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH2 expression by immunohistochemistry (Stormorken AT et al. J Clin Oncol. 2005 Jul 20;23(21):4705-12; Grindedal EM et al. Cancer Epidemiol Biomarkers Prev. 2009 Sep;18(9):2460-7; Sjursen W et al. J Med Genet. 2010 Sep;47(9):579-85). 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