rs863224630
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000251.3(MSH2):c.1759+3A>G variant causes a splice donor region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 8.1e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MSH2
NM_000251.3 splice_donor_region, intron
NM_000251.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.4103
2
Clinical Significance
Conservation
PhyloP100: 4.64
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 Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-47471065-A-G is Pathogenic according to our data. Variant chr2-47471065-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1175146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47471065-A-G is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.38). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.1759+3A>G | splice_donor_region_variant, intron_variant | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.1759+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.10e-7 AC: 1AN: 1234568Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0AN XY: 625874
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
1234568
Hom.:
Cov.:
19
AF XY:
AC XY:
0
AN XY:
625874
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | This sequence change falls in intron 11 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1175146). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 11 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 03, 2024 | The c.1759+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 11 in the MSH2 gene. This nucleotide position is not well conserved in available vertebrate species. This variant has been identified in conjunction with another MSH2 variant in an individual who met clinical criteria for constitutional mismatch repair deficiency syndrome (external laboratory communication). This variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MSH2 or MSH2/MSH6 expression by immunohistochemistry (external laboratory communication). In silico splice site analysis for this alteration is inconclusive and direct evidence is insufficient at this time (Ambry internal data). However, external laboratory RNA studies have reported that this alteration results in abnormal splicing in the set of samples tested. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.