2-47470963-A-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000251.3(MSH2):c.1662-2A>T variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000251.3 splice_acceptor, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1263680Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0AN XY: 639276
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change affects an acceptor splice site in intron 10 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1396678). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 11809679, 24090359). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.1662-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 11 in the MSH2 gene. This alteration was identified as somatic in a colorectal tumor that demonstrated loss of MSH2 and MSH6 protein expression on immunohistochemistry (IHC) (Ambry internal data). A nearby alteration at the same canonical splice acceptor site, c.1662-1G>A, has been reported as homozygous in a patient with constitutional mismatch repair deficiency (CMMRD) syndrome and analysis of RNA from this patient confirmed skipping of exons 11 and 12 resulting in a truncated protein (Whiteside D et al. Cancer Res. 2002 Jan 15;62(2):359-62). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.