rs587779164
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000251.3(MSH2):c.528_529delTG(p.Cys176fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000251.3 frameshift
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 genome
ClinVar
Submissions by phenotype
Lynch syndrome Pathogenic:4
Variant summary: The MSH2 c.528_529delTG (p.Cys176Terfs) variant results in premature termination at codon 176, predicted to cause a truncated or absent MSH2 protein due to nonsense mediated decay, which is a commonly known mechanism for Lynch syndrome. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln344X, p.Arg383X, p.Glu569fs). Mutation Taster predicts a damaging outcome for this variant. This variant was not found in 121412 control chromosomes, but has been cited in at least 3 patients from the literature. In addition, several clinical laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant was classified as pathogenic. -
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This variant deletes 2 nucleotides in exon 3 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 11208710, 21642682, 26437257, 28874130), with tumor data demonstrating loss of MSH2 and MSH6 protein via immunohistochemistry and/or high microsatellite instability (PMID: 11208710, 26437257, 28874130). 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. -
Coding sequence variation resulting in a stop codon -
not provided Pathogenic:3
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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 at significant frequency 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: 11208710, 36139606, 21642682, 28874130, 32917768, 26437257) -
This frameshift variant causes the premature termination of MSH2 protein synthesis. In addition, it has been reported in families with Lynch Syndrome or Lynch Syndrome-related cancers in the published literature (PMIDs: 11208710 (2001), 21642682 (2011), 26437257 (2015), and 28874130 (2017)). Based on the available information, this variant is classified as pathogenic. -
Lynch syndrome 1 Pathogenic:2
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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Hereditary cancer-predisposing syndrome Pathogenic:2
The c.528_529delTG pathogenic mutation (also known as p.C176*), located in coding exon 3 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 528 to 529. This changes the amino acid from a cysteine to a stop codon within coding exon 3. This mutation was reported in a proband from an HNPCC family whose tumor testing showed high microsatellite instability (MSI-H) (Terdiman JP et al. Gastroenterology. 2001 Jan;120(1):21-30). 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 deletes 2 nucleotides in exon 3 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 11208710, 21642682, 26437257, 28874130). 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. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Cys176*) 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 or Lynch syndrome-related cancers (PMID: 11208710, 21642682, 26437257, 28874130). ClinVar contains an entry for this variant (Variation ID: 91126). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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