chr2-47475024-G-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 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
Genomes: not found (cov: 32)
Consequence
MSH2
NM_000251.3 splice_acceptor, intron
NM_000251.3 splice_acceptor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.13
Genes affected
MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08734403 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.4, offset of -38, new splice context is: tatatctgtttattattcAGtat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-47475024-G-A is Pathogenic according to our data. Variant chr2-47475024-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 90773.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475024-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-47475024-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:12
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Lynch syndrome Pathogenic:4
| Likely pathogenic, reviewed by expert panel | curation | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Jun 21, 2019 | Interrupts canonical donor splice site - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 05, 2017 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | May 01, 2018 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 09, 2023 | 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
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 16, 2019 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 30, 2016 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | MSH2: PVS1, PM2, PS4:Moderate - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 08, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 02, 2021 | 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
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 06, 2024 | 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
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 03, 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. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | 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; Invitae). It has also been observed to segregate with disease in related individuals. 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
DS_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at