rs755583143
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_ModeratePP3
The NM_000251.3(MSH2):c.942+2_942+6del variant causes a splice donor, splice donor 5th base, intron change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 0)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MSH2
NM_000251.3 splice_donor, splice_donor_5th_base, intron
NM_000251.3 splice_donor, splice_donor_5th_base, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.70
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 Uncertain_significance. Variant got 3 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
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.942+2_942+6del | splice_donor_variant, splice_donor_5th_base_variant, intron_variant | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.942+2_942+6del | splice_donor_variant, splice_donor_5th_base_variant, intron_variant | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 0
GnomAD3 genomes
?
Cov.:
0
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 474794Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 241654
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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474794
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0
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241654
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GnomAD4 genome ? Cov.: 0
GnomAD4 genome
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0
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 11, 2020 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Donor and acceptor splice site variants 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 has not been reported in the literature in individuals with MSH2-related conditions. However, variants that disrupt this splice site have been observed in individuals with clinical features of Lynch syndrome (PMID: 25980754, 20591884, 12624141, 18566915). ClinVar contains an entry for this variant (Variation ID: 237416). This variant is present in population databases (rs755583143, ExAC 0.1%). This sequence change affects a donor splice site in intron 5 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. - |
Computational scores
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Name
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Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at