rs587779112

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000233146.7(MSH2):​c.1827del​(p.His610ThrfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. A609A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

MSH2
ENST00000233146.7 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: -0.0730
Variant links:
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]

Genome browser will be placed here

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 2-47475091-CT-C is Pathogenic according to our data. Variant chr2-47475091-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 90796.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475091-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH2NM_000251.3 linkuse as main transcriptc.1827del p.His610ThrfsTer25 frameshift_variant 12/16 ENST00000233146.7 NP_000242.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkuse as main transcriptc.1827del p.His610ThrfsTer25 frameshift_variant 12/161 NM_000251.3 ENSP00000233146 P1P43246-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 15, 2020This variant deletes 1 nucleotide in exon 12 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 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. -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 11, 2021The c.1827delT pathogenic mutation, located in coding exon 12 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 1827, causing a translational frameshift with a predicted alternate stop codon (p.H610Tfs*25). 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. -
Hereditary nonpolyposis colon cancer Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 17, 2023Variant summary: MSH2 c.1827delT (p.His610ThrfsX25) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 251474 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1827delT in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Lynch syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Aug 03, 2023This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Lynch syndrome Pathogenic:1
Pathogenic, reviewed by expert panelresearchInternational Society for Gastrointestinal Hereditary Tumours (InSiGHT)Sep 05, 2013Coding sequence variation introducing premature termination codon -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 01, 2022This variant has not been reported in the literature in individuals affected with MSH2-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90796). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His610Thrfs*25) 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). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587779112; hg19: chr2-47702230; API