chr2-47470964-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000251.3(MSH2):c.1662-1G>A variant causes a splice acceptor 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)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MSH2
NM_000251.3 splice_acceptor
NM_000251.3 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.22
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 2-47470964-G-A is Pathogenic according to our data. Variant chr2-47470964-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 90727.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47470964-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.1662-1G>A | splice_acceptor_variant | ENST00000233146.7 | NP_000242.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.1662-1G>A | splice_acceptor_variant | 1 | NM_000251.3 | ENSP00000233146 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1278470Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0AN XY: 645932
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
AC:
0
AN:
1278470
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Cov.:
20
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0
AN XY:
645932
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Lynch syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 10, 2017 | The c.1662-1G>A variant in MSH2 has been reported as a germline variant in the h omozygous state in 1 individual with T-cell acute lymphoblastic leukemia and mul tiple cafe-au-lait spots (Whiteside 2002) and was absent in large population stu dies. This variant occurs in the invariant region (+/- 1,2) of the splice consen sus sequence and has shown to cause exon 11 skipping in blood derived patient RN A and results in an absent MSH2 protein (Whiteside 2002). Heterozygous loss of f unction of the MSH2 gene is an established disease mechanism in individuals with Lynch syndrome. Furthermore, the c.1662-1G>A variant has been classified as pat hogenic on Sept. 5th, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107248.2). In summary, this variant meets criteria to be classified as pa thogenic for Lynch syndrome in an autosomal dominant manner based upon impact to the protein, functional studies and absence from controls. - |
Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Variant causes splicing aberration (full inactivation of variant allele) - |
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. - |
Lynch-like syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Constitutional Genetics Lab, Leon Berard Cancer Center | Jul 01, 2019 | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 18, 2022 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 11809679, 24090359). ClinVar contains an entry for this variant (Variation ID: 90727). Disruption of this splice site has been observed in individual(s) with MSH2-related conditions (PMID: 11809679, 28944238). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 10 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 28, 2024 | The c.1662-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 11 of the MSH2 gene. This variant has been identified in the homozygous state in an individual with features consistent with constitutional mismatch repair deficiency syndrome (Whiteside D et al. Cancer Res. 2002 Jan; 62(2):359-62). In addition, RNA studies demonstrated that this alteration results in abnormal splicing (Whiteside D et al. Cancer Res. 2002 Jan; 62(2):359-62; Ambry internal data). This mutation was also identified in 1/333 individuals with early onset colon cancer and in 0/93 unaffected controls (DeRycke MS et al. Mol Genet Genomic Med 2017 Sep;5:553-569). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. 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. - |
Mismatch repair cancer syndrome 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 15, 2002 | - - |
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_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at