rs587779110
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000251.3(MSH2):c.1760-1G>A 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 Likely pathogenic (★★★).
Frequency
Consequence
NM_000251.3 splice_acceptor, intron
Scores
Clinical Significance
Conservation
Publications
- Lynch syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
- Lynch syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
- Muir-Torre syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
- mismatch repair cancer syndrome 1Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- mismatch repair cancer syndrome 2Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
- ovarian cancerInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- malignant pancreatic neoplasmInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- prostate cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- rhabdomyosarcomaInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
- breast cancerInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
- hereditary breast carcinomaInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MSH2 | NM_000251.3 | c.1760-1G>A | splice_acceptor_variant, intron_variant | Intron 11 of 15 | ENST00000233146.7 | NP_000242.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MSH2 | ENST00000233146.7 | c.1760-1G>A | splice_acceptor_variant, intron_variant | Intron 11 of 15 | 1 | NM_000251.3 | ENSP00000233146.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
Lynch syndrome Pathogenic:4
Interrupts canonical donor splice site -
MSH2 NM_000251.2:c.1760-1G>A has a 98.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214. -
The c.1760-1G>A variant in MSH2 has been reported in 1 individual with MSH2-asso ciated cancer (Hu et al. 2011) and was absent from large population studies. Thi s variant occurs in the invariant region (+/- 1,2) of the splice consensus seque nce and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the MSH2 gene is an established diseas e mechanism in Lynch syndrome. In addition, this variant was classified as likel y pathogenic on Sept 13, 2013 by the ClinGen-approved InSiGHT expert panel (Clin Var SCV000107297.2). In summary, although additional studies are required to ful ly establish its clinical significance, the c.1760-1G>A variant is likely pathog enic. ACMG/AMP Criteria applied: PVS1; PM2. -
The c.1760-1G>A variant of the MSH2 gene is predicted to affect mRNA splicing and result in an absent or disrupted protein product. This variant has been reported in individuals with Lynch syndrome (PMID: 20459533, 22166501). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in MSH2 are known to be pathogenic (PMID: 15849733). Therefore, the c.1760-1G>A variant of MSH2 gene is classified as likely pathogenic. -
not provided Pathogenic:3
The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient in literature, and not found in general population data. -
This variant is denoted MSH2 c.1760-1G>A or IVS11-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 11 of the MSH2 gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least one proband meeting Amsterdam criteria for Lynch syndrome (Hu 2011). Based on the currently available information, we consider MSH2 c.1760-1G>A to be a likely pathogenic variant. -
MSH2: PVS1, PM2, PS4:Moderate -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant causes a G to A nucleotide substitution at the -1 position of intron 11 of the MSH2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. . This variant has been reported in individuals affected with Lynch syndrome (PMID: 20459533, 22166501). 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 Likely Pathogenic. -
The c.1760-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide before coding exon 12 of the MSH2 gene. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated high microsatellite instability and/or loss of MSH2/MSH6 expression by immunohistochemistry (Ambry internal data). This variant has also been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH2/MSH6 expression by immunohistochemistry (Barrow E et al. Histopathology, 2010 Feb;56:331-44; Ambry internal data). In addition, this variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome (Hu P et al. Ann. Clin. Lab. Sci., 2011;41:321-30; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor 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 a disease-causing mutation. -
Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: MSH2 c.1760-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. Three predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 1612342 control chromosomes (gnomAD v4). c.1760-1G>A has been reported in the literature in individuals affected with Lynch Syndrome or Lynch-syndrome associated cancers (e.g., Hu_2011, Barrow_2010, Kansikas_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20459533, 22166501, 36875157, 31447099). ClinVar contains an entry for this variant (Variation ID: 90773). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Lynch syndrome 1 Pathogenic:1
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. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change affects an acceptor splice site in intron 11 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: 20459533, 22166501; internal data). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. ClinVar contains an entry for this variant (Variation ID: 90773). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at