rs863224481
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000251.3(MSH2):c.141_154delCGAGGACGCGCTGC(p.Glu48GlyfsTer29) 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 Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Lynch syndrome Pathogenic:1
This sequence change deletes 14 nucleotides from exon 1 of the MSH2 mRNA (c.141_154delCGAGGACGCGCTGC), causing a frameshift at codon 48. This creates a premature translational stop signal (p.Glu48Glyfs*29) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 216052). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu48Glyfs*29) 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
The c.141_154delCGAGGACGCGCTGC pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a deletion of 14 nucleotides at nucleotide positions 141 to 154, causing a translational frameshift with a predicted alternate stop codon (p.E48Gfs*29). 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