rs1060502023
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong
The NM_000251.3(MSH2):c.1510+2T>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,578 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★).
Frequency
Consequence
NM_000251.3 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.1510+2T>C | splice_donor_variant | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.1510+2T>C | splice_donor_variant | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461578Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727108
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Lynch syndrome 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jul 16, 2021 | This MSH2 variant is absent in a large population dataset and has been reported in ClinVar. This variant destroys the native donor (5') splice site for exon 9 and is predicted to cause aberrant mRNA splicing. It has been reported in an individual with colorectal cancer (CRC) who underwent targeted germline DNA sequencing. We consider c.1510+2T>C to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 23, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 02, 2023 | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 05, 2019 | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 13, 2023 | This sequence change affects a donor splice site in intron 9 of the MSH2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28944238, 30877237, 33468869). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 408532). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2024 | The c.1510+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 9 in the MSH2 gene. In one study, this alteration was identified in 1/1231 colorectal cancer cases and was not present in the control group (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This alteration was reported in a proband whose colorectal tumor demonstrated loss of MSH2 staining on immunohistochemistry (IHC) (Pearlman R et al. J Med Genet, 2019 07;56:462-470). This alteration has also been identified in a proband whose colorectal tumor demonstrated loss of both MSH2 and MSH6 staining on IHC (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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 likely pathogenic/a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at