MSH2 c.942+20_942+29del, p.?
NM_000251.3:c.942+20_942+29del
Likely Benign
The MSH2 c.942+20_942+29del variant is classified as Likely Benign based on absence from population databases (PM2_supporting), lack of predicted splicing impact (BP4), intronic location beyond the canonical splice region (BP7), and benign assertions in ClinVar (BP6).
ACMG/AMP Criteria Applied
PM2
BP4
BP7
Genetic Information
Gene & Transcript Details
Gene
MSH2
Transcript
NM_000251.3
MANE Select
Total Exons
16
Strand
Forward (+)
Reference Sequence
NC_000002.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000251.2 | RefSeq Select | 16 exons | Forward |
| NM_000251.1 | Alternative | 16 exons | Forward |
Variant Details
HGVS Notation
NM_000251.3:c.942+20_942+29del
Protein Change
?
Location
Exon 5
(Exon 5 of 16)
5'Exon Structure (16 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000251.3
Genome Browser
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HGVS InputNM_000251:c.942+20_942+29del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Likely Benign
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
3 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (1 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Likely Benign (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP MSH2 guidelines, PVS1 applies to canonical ±1–2 splice site or truncating variants. The rule for PVS1 is: 'Very Strong Nonsense/frameshift variant introducing Premature Termination Codon ≤ codon 891 in MSH2 or IVS±1/2 splice variants.' The evidence for this variant shows an intronic deletion at +20 to +29. Therefore, this criterion is not applied because the variant does not affect canonical splice sites or introduce a truncation.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP MSH2 guidelines, PS1 applies to predicted missense substitutions encoding the same amino acid change. The rule for PS1 is: 'Strong – Equivalent amino acid change as a known pathogenic missense.' The evidence for this variant shows no amino acid change (intronic). Therefore, this criterion is not applied because it is not a missense variant.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP MSH2 guidelines, PS2 applies to de novo occurrences. The rule for PS2 is: 'Very Strong – ≥4 de novo points.' The evidence for this variant shows no de novo data. Therefore, this criterion is not applied due to absence of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP MSH2 guidelines, PS3 applies to validated functional assays. The rule for PS3 is: 'Strong – Calibrated functional assays with odds >18.7.' The evidence for this variant shows no functional characterization. Therefore, this criterion is not applied because functional assay data are missing.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 applies to case-control data showing significant enrichment. The rule for PS4 is: 'Strong – Increased prevalence in affected vs controls.' The evidence for this variant shows no case-control data. Therefore, this criterion is not applied due to lack of statistical evidence.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants in mutational hotspots or critical functional domains. The rule for PM1 is: 'Moderate – Located in a well‐established functional domain without benign variation.' The evidence for this variant shows no mapping to a functional domain. Therefore, this criterion is not applied because domain impact is not established.
PM2
PM2 (Supporting) Strength Modified
According to VCEP MSH2 guidelines, the rule for PM2 is: 'Supporting – Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset.' The evidence for this variant shows absence in gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP MSH2 guidelines, PM3 applies to recessive in trans occurrences. The rule for PM3 is: 'Moderate/Strong/Very Strong based on points for trans observations.' The evidence for this variant shows no co-occurrence data. Therefore, this criterion is not applied due to absence of in trans data.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes. The rule for PM4 is: 'Moderate – In-frame indels or stop-loss leading to protein length change.' The evidence for this variant shows an intronic deletion without coding impact. Therefore, this criterion is not applied because there is no protein alteration.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP MSH2 guidelines, PM5 applies to different missense changes at the same residue. The rule for PM5 is: 'Moderate – Missense change at residue with known pathogenic missense.' The evidence for this variant shows no missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP MSH2 guidelines, PM6 applies to presumed de novo cases without confirmation. The rule for PM6 is: 'Supporting – 0.5 de novo points.' The evidence for this variant shows no de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 applies to co-segregation with disease. The rule for PP1 is: 'Supporting/Moderate/Strong based on Bayes LR from segregation.' The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation. The rule for PP2 is: 'Supporting – Missense in gene with <10% benign missense.' The evidence for this variant shows an intronic deletion. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP MSH2 guidelines, PP3 applies to predicted splice defects by SpliceAI (delta ≥0.2). The rule for PP3 is: 'Supporting – Predicted splice defect at non-canonical site.' The evidence for this variant shows SpliceAI maximum delta = 0. Therefore, this criterion is not applied because in silico predicts no splicing impact.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP MSH2 guidelines, PP4 applies to tumor MSI/IHC phenotype. The rule for PP4 is: 'Supporting/Moderate/Strong based on number of independent MSI-H tumors or protein loss.' The evidence for this variant shows no tumor data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies to pathogenic assertion by a reputable source. The rule for PP5 is: 'Supporting – Reputable source reports pathogenic without evidence.' The evidence for this variant shows ClinVar reports benign/likely benign. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP MSH2 guidelines, BA1 applies to allele frequency ≥0.1%. The rule for BA1 is: 'Stand Alone – GnomAD v4 Grpmax filtering allele frequency ≥0.001.' The evidence for this variant shows frequency = 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP MSH2 guidelines, BS1 applies to allele frequency ≥0.01%. The rule for BS1 is: 'Strong – GnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001.' The evidence for this variant shows frequency = 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP MSH2 guidelines, BS2 applies to trans co-occurrence with pathogenic variant. The rule for BS2 is: 'Strong – Co-occurrence in trans in older LS patient without CMMRD.' The evidence for this variant shows no co-occurrence data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP MSH2 guidelines, BS3 applies to functional assays showing no effect. The rule for BS3 is: 'Strong – Calibrated functional assays with odds ≤0.05 or synonymous/intronic with no mRNA aberration.' The evidence for this variant shows no assay data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 applies to lack of segregation. The rule for BS4 is: 'Strong – Bayes LR <0.05 for co-segregation.' The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense in gene where truncating causes disease. The rule for BP1 is: 'Supporting – Missense variant in gene with pathogenic truncations.' The evidence for this variant shows an intronic deletion. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies to cis-occurrence with pathogenic variant. The rule for BP2 is: 'Supporting – Observed in cis with pathogenic variant.' The evidence for this variant shows no cis-occurrence data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. The rule for BP3 is: 'Supporting – In-frame indel in repetitive region.' The evidence for this variant shows a non-coding intronic deletion. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, BP4 applies to intronic variants with no splicing impact by SpliceAI. The rule for BP4 is: 'Supporting – SpliceAI predicts no splicing impact with delta score ≤0.1.' The evidence for this variant shows SpliceAI maximum delta = 0. Therefore, this criterion is applied at Supporting strength because computational evidence indicates no splicing effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies to variant found in a case with alternative molecular cause. The rule for BP5 is: 'Supporting – Found with alternative molecular cause inconsistent with gene.' The evidence for this variant shows no such case data. Therefore, this criterion is not applied.
BP7
BP7 (Supporting)
According to VCEP MSH2 guidelines, BP7 applies to intronic variants at or beyond +7. The rule for BP7 is: 'Supporting – A synonymous or intronic variant at or beyond -21/+7.' The evidence for this variant shows location +20 to +29. Therefore, this criterion is applied at Supporting strength because it lies outside the critical splicing region.