MSH2 c.942+19_942+29del, p.?
NM_000251.3:c.942+19_942+29del
Likely Benign
This intronic deletion c.942+19_942+29del in MSH2 is absent from population databases, is predicted by SpliceAI to have no splicing impact, and is reported as benign/likely benign by reputable sources. No pathogenic evidence is present. Based on multiple supporting benign criteria (BP4, BP6, BP7) and no applied pathogenic criteria, the variant is classified as Likely Benign.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
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+19_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+19_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 2 submitter reviews in ClinVar
Submitter Breakdown
1 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 Likely Benign (1 clinical laboratories) and as Likely benign (1 clinical laboratories) and as 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
Functional Summary
The MSH2 942+19_942+29del variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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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 guidelines, the rule for PVS1 is: "Variants at IVS±1 or IVS±2 where exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD." The evidence for this variant shows: it is an intronic deletion at positions +19 to +29, not affecting canonical splice sites or coding sequence. Therefore, this criterion is not applied because the variant does not meet any PVS1 conditions (not a null variant at canonical splice sites or frameshift).
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established as Pathogenic." The evidence for this variant shows: it is an intronic deletion with no amino acid change. Therefore, this criterion is not applied because the variant does not result in an amino acid substitution matching a known pathogenic change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo testing or parental origin data are available. Therefore, this criterion is not applied because de novo status cannot be evaluated without parental testing.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: no functional assays have been performed. Therefore, this criterion is not applied due to lack of functional study data.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence of the variant in affected individuals is significantly increased compared to controls." The evidence for this variant shows: no case-control or cohort data are available. Therefore, this criterion is not applied because prevalence in affected individuals cannot be assessed.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: the deletion is intronic and not located within a defined critical functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP 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: it is not observed in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases, meeting PM2_Supporting.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no information on trans occurrence with a pathogenic allele. Therefore, this criterion is not applied because allelic configuration data are missing.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in non-repeat regions or stop-loss variants." The evidence for this variant shows: it is an intronic deletion that does not alter protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before." The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no parental data. Therefore, this criterion is not applied because de novo status cannot be assumed without parental testing.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no family segregation studies. Therefore, this criterion is not applied because segregation data are unavailable.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation." The evidence for this variant shows: it is not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Predicted splice defect for non-canonical splice nucleotides using SpliceAI with delta score ≥ 0.2." The evidence for this variant shows: SpliceAI maximum delta score is 0.00, indicating no predicted splice impact. Therefore, this criterion is not applied because computational predictions do not support a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting evidence from a relevant phenotype (e.g., CRC/MSI-H tumors)." The evidence for this variant shows: no tumor phenotype or MSI data are available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source asserts pathogenic classification without available evidence." The evidence for this variant shows: reputable sources classify it as benign/likely benign. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone GnomAD v4 Grpmax filtering allele frequency ≥ 0.001 (0.1%)." The evidence for this variant shows: it is absent from gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong GnomAD v4 Grpmax filtering allele frequency ≥ 0.0001 and < 0.001." The evidence for this variant shows: it is absent from gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Co-occurrence in trans with a pathogenic variant in LS cancer patients." The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Calibrated functional assays show no damaging effect OR synonymous/intronic variants with no mRNA aberration." The evidence for this variant shows: no mRNA or functional assays have been conducted. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation studies. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants are pathogenic." The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant disease." The evidence for this variant shows: no trans co-occurrence data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive regions without a known functional impact." The evidence for this variant shows: it is an intronic deletion outside repetitive coding regions. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score ≤ 0.1." The evidence for this variant shows: SpliceAI delta score = 0.00 indicating no impact on splicing. Therefore, this criterion is applied at Supporting strength because computational evidence supports no effect on splicing.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular diagnosis is reported. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign or likely benign without available evidence." The evidence for this variant shows: ClinVar entries from three clinical laboratories classify it as benign/likely benign. Therefore, this criterion is applied at Supporting strength because a reputable source asserts benign status.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "Supporting A synonymous or intronic variant at or beyond -21/+7 that does not affect splicing." The evidence for this variant shows: the deletion spans +19 to +29, beyond +7, with no predicted splice impact. Therefore, this criterion is applied at Supporting strength because it meets location and lack-of-splicing-impact requirements.