MSH2 c.212-6_212-4del, p.?
NM_000251.3:c.212-6_212-4del
Likely Benign
This intronic MSH2 variant is classified as Likely Benign based on two VCEP-supported benign criteria (BP4 and BP6) and absence of any evidence for pathogenicity.
ACMG/AMP Criteria Applied
BP4
BP6
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.212-6_212-4del
Protein Change
?
Location
Exon 1
(Exon 1 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.212-6_212-4del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00372%
Rare
Highest in Population
Admixed American
0.00665%
Rare
Global: 0.00372%
Admixed American: 0.00665%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 107442Alt: 4Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00372%, 4/107442 alleles, homozygotes = 0) and at a higher frequency in the Admixed American population (MAF= 0.00665%, 1/15028 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
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 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 212-6_212-4del 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 a,c 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 at positions IVS-6 to -4, outside the ±1 or ±2 splice site positions. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as an established Pathogenic variant.' The evidence for this variant shows no amino acid change (intronic deletion). Therefore, this criterion is not applied.
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.' There are no de novo data for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product.' No functional studies have been performed for this variant. Therefore, this criterion is not applied.
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 with controls.' No case-control data are available. Therefore, this criterion is not applied.
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.' This intronic variant is not in a defined hot spot or functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2_Supporting is: 'Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset.' The evidence shows an allele frequency of ~4/107,442 (~1/26,860), which is above 1/50,000. Therefore, this criterion is not applied.
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.' There is no evidence of recessive in trans occurrence. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame indels or stop-loss variants.' This intronic deletion 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.' This variant is intronic, not missense. 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.' There is no de novo evidence. Therefore, this criterion is not applied.
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.' No segregation data are available. Therefore, this criterion is not applied.
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.' This variant is intronic. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3_Supporting is: 'Predicted splice defect for non-canonical splice nucleotides using SpliceAI with delta score ≥0.2.' The SpliceAI delta score for this variant is 0.09, below the 0.2 threshold. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history highly specific for a disease with a single genetic etiology.' No detailed phenotype/family history is available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is deprecated and should not be used. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'GnomAD v4 Grpmax filtering allele frequency ≥0.001 (0.1%).' The observed frequency is 0.0000372 (<0.001). Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'GnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001.' The observed frequency is 0.0000372, below 0.0001. 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 known pathogenic sequence variant in the same gene in a patient meeting LS criteria.' No such co-occurrence data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3_Strong is: 'Calibrated functional assays with odds for pathogenicity ≤0.05 OR synonymous/intronic variants with no mRNA aberration.' No mRNA assays have been performed. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Lack of co-segregation with disease in pedigree(s).' No segregation data are available. 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 for which primarily truncating variants cause disease.' This variant is intronic. 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 gene.' No such data are available. 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 a repetitive region without a known function.' This intronic deletion is not in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score ≤0.1.' The evidence shows a SpliceAI delta score of 0.09. Therefore, this criterion is applied at Supporting strength.
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.' No such case data are available. 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, but evidence not available for independent evaluation.' ClinVar entries report this variant as Likely benign and Benign from two labs. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous or intronic variant at or beyond -21/+7 positions.' This variant lies at -6 to -4, within the critical splice region. Therefore, this criterion is not applied.