rs267607940
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000251.3(MSH2):c.1076+1G>A variant causes a splice donor, 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
Genomes: not found (cov: 32)
Consequence
MSH2
NM_000251.3 splice_donor, intron
NM_000251.3 splice_donor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.81
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 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-47416430-G-A is Pathogenic according to our data. Variant chr2-47416430-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 90519.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47416430-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MSH2 | NM_000251.3 | c.1076+1G>A | splice_donor_variant, intron_variant | ENST00000233146.7 | NP_000242.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MSH2 | ENST00000233146.7 | c.1076+1G>A | splice_donor_variant, intron_variant | 1 | NM_000251.3 | ENSP00000233146.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Lynch syndrome 1 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 23, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 31, 2023 | This variant is considered 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. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. - |
Lynch syndrome Pathogenic:2
| Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Variant causes splicing aberration, 2 MSI-H tumours, co-segregation with disease & MAF 0.00 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 14, 2020 | Variant summary: MSH2 c.1076+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 5' splicing donor site. These predictions were confirmed by publications reporting experimental evidence demonstrating that this variant results in exon 6 skipping, which is predicted to result in a frame-shift at the protein level (Auclair_2006, Fernandez-Rozadilla_2019). The variant was absent in 251386 control chromosomes (gnomAD). The variant, c.1076+1G>A, has been reported in the literature in multiple individuals affected with Lynch Syndrome and related tumor phenotypes (e.g. Wang_1999, Fernandez-Rozadilla_2019). Four submitters, including one expert panel (InSiGHT) have provided clinical-significance assessments for this variant in ClinVar, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 09, 2023 | The MSH2 c.1076+1G>A variant disrupts a canonical splice-donor site and interferes with normal MSH2 mRNA splicing. This variant has been reported in the published literature in several individuals and families affected with Lynch syndrome associated cancers including colorectal cancer (PMIDs: 10480359 (1999), 15955785 (2005), 16034045 (2005), 16395668 (2006), 20587412 (2010), 29360550 (2018), 31366136 (2019)), prostate cancer (PMID: 19723918 (2009)), and ovarian cancer (PMID: 36169650 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2024 | Canonical splice site variant demonstrated to result in aberrant splicing and predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 16395668, 31366136); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 21404117, 16034045, 31830689, 16395668, 25525159, 25980754, 19723918, 20587412, 15955785, 10480359, 21642682, 28449805, 29360550, 29887214, 31615790, 34178123, 30787465, 36243179, 36169650, 31366136) - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 04, 2023 | This sequence change affects a donor splice site in intron 6 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. 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: 10480359, 15955785, 19723918, 21642682, 28449805, 31366136). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90519). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16395668, 31366136; Invitae). 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 | Apr 05, 2023 | The c.1076+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the MSH2 gene. This mutation has been identified in multiple individuals that met Amsterdam I/II criteria for Lynch syndrome and/or had tumors that demonstrated loss of MSH2/MSH6 expression on immunohistochemistry (Ambry internal data; Wang Q et al. Hum Genet 1999;105:79-85; Stormorken AT et al. J. Clin. Oncol., 2005 Jul;23:4705-12; Mueller-Koch Y et al. Gut, 2005 Dec;54:1733-40; Sjursen W et al. J. Med. Genet., 2010 Sep;47:579-85; Bonadona V et al. JAMA, 2011 Jun;305:2304-10; Sunga AY et al. Cancer Genet, 2017 Apr;212-213:1-7; Shirts BH et al. Am. J. Hum. Genet., 2018 07;103:19-29; Wardell CP et al. J. Hepatol., 2018 05;68:959-969; Fernandez-Rozadilla C et al. Cancers (Basel), 2019 Jul;11:1081; Yang M et al. Ther Adv Med Oncol, 2021 Jun;13:17588359211023290). This alteration has also been shown to result in exon skipping by mRNA analysis (Auclair J et al. Hum Mutat. 2006; 27:145-54; Fernandez-Rozadilla C et al. Cancers (Basel), 2019 Jul;11:1081). 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. - |
Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
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
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_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at