chr2-47414419-G-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePP3_StrongPP5_Very_Strong
The NM_000251.3(MSH2):c.942+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. 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: 𝑓 0.0 ( 0 hom., cov: 0)
Exomes 𝑓: 0.00024 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MSH2
NM_000251.3 splice_donor
NM_000251.3 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.59
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 14 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.05311943 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 2-47414419-G-T is Pathogenic according to our data. Variant chr2-47414419-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91247.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47414419-G-T is described in Lovd as [Pathogenic]. Variant chr2-47414419-G-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.942+1G>T | splice_donor_variant | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.942+1G>T | splice_donor_variant | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 31296Hom.: 0 Cov.: 0 FAILED QC
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000236 AC: 112AN: 474546Hom.: 0 Cov.: 25 AF XY: 0.000240 AC XY: 58AN XY: 241532
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GnomAD4 genome ? Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 31320Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 13930
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:7
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Lynch syndrome Pathogenic:2
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 | Oct 14, 2019 | The c.942+1G>T variant in MSH2 has been reported in 1 individual affected with Lynch syndrome (Nilbert 2009) and was absent from large population studies. This variant was classified as Likely Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 91247). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the MSH2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. Other variants affecting the same splice site have been reported in ClinVar (Pathogenic or Likely Pathogenic). In summary, the c.942+1G>T variant meets criteria to be classified as pathogenic for Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PM5. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 18, 2019 | The c.942+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 5 in the MSH2 gene. This alteration was identified in one Danish kindred suspicious for hereditary colorectal cancer (Nilbert M, Fam. Cancer 2009 ; 8(1):75-83). In addition, this alteration has been identified in patients with Lynch syndrome associated cancers whose tumors demonstrated loss of MSH2 and MSH6 protein on IHC analysis (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site; however, direct evidence experimental is unavailable. 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 08, 2022 | This variant causes a G to T nucleotide substitution at the +1 position of intron 5 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: 18566915, 27601186). 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. - |
Lynch syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 28, 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. Functional studies indicate this variant impacts protein function [PMID: 8062247]. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | MSH2: PVS1, PP4:Moderate - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change affects a donor splice site in intron 5 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened 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: 18566915, 27601186). ClinVar contains an entry for this variant (Variation ID: 91247). Studies have shown that disruption of this splice site results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (Invitae). This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Leu310Arg) have been determined to be pathogenic (PMID: 22290698, 30374176; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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
MutationTaster
Benign
D;D;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