NM_000179.3:c.4001+32_4001+35dup is an intronic duplication in MSH6 intron 9, located 32 bases downstream of exon 9. This variant is observed in gnomAD v4.1 at an allele frequency of 0.00996% (159/1,597,002 alleles, 0 homozygotes) with a grpmax filtering allele frequency of 0.0203%.1 SpliceAI predicts no splicing impact (max delta score = 0.00), meeting VCEP BP4_Supporting for intronic variants.2 The variant is intronic at position c.4001+32, beyond the +7 boundary, satisfying VCEP BP7_Supporting.3 This variant has been reported in ClinVar as Likely benign by 4 clinical laboratories and Benign by 1 clinical laboratory (VariationID 89502, 1-star review status).4 No pathogenic criteria are met. VCEP PVS1 is not applicable as the variant is a deep intronic duplication without evidence of a splicing aberration. No variant-specific functional, segregation, or tumor phenotype data are available. Applying the InSiGHT MSH6 VCEP v2.0 combination rules: BP4_Supporting + BP7_Supporting (≥2 benign supporting criteria) classifies this variant as Likely Benign (Rule 19).5
MSH6
Final classification
Likely Benign
MSH6 c.4001+32_4001+35dup · p.?
MSH6
NM_000179.3:c.4001+32_4001+35dup is an intronic duplication in MSH6 intron 9, located 32 bases downstream of exon 9.
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 2.0 v2.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: BP4 supporting, BP7 supporting; maps to Likely Benign.
Classification rationale
BP4BP7
Likely Benign
MSH6 c.4001+32_4001+35dup
BP4 + BP7
→
Likely Benign
Gene diagram
· NM_000179.3 · variants mapped to exon structure
MSH6
NM_000179.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 14 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
BP4
supporting
Benign
VCEP BP4_Supporting for intronic variants: SpliceAI predicts no splicing impact with delta score ≤ 0.1 as per Walker et al 2023. This intronic duplication at c.4001+32_4001+35 has a SpliceAI max delta score of 0.00, indicating no predicted effect on splicing. The variant also satisfies BP7; BP4 and BP7 may both be applied per VCEP rules.
SpliceAI max delta score = 0.00 (≤ 0.1 threshold)No predicted splicing impact for this intronic variant
✓
BP7
supporting
Benign
VCEP BP7_Supporting: synonymous or intronic variant at or beyond -21/+7 (5′/3′ exonic). NM_000179.3:c.4001+32_4001+35dup is an intronic variant located 32 bases downstream of exon 9, well beyond the +7 boundary. This criterion may be applied alongside BP4 per VCEP rules.
Intronic variant at c.4001+32located 32 bases into intron 9beyond the +7 splice boundary
Assessed · not applied
Pathogenic
PVS1
NM_000179.3:c.4001+32_4001+35dup is an intronic duplication located 32 bases downstream of exon 9.
PS1
VCEP PS1 requires either a same-amino-acid missense change with a different nucleotide, or a variant affecting the same non-canonical splice nucleotide as a known pathogenic splice variant with similar or worse SpliceAI prediction.
PS2
No de novo observation data is available for this variant.
PS3
No variant-specific functional data exists for NM_000179.3:c.4001+32_4001+35dup.
PM2
VCEP PM2_Supporting requires absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4.
PP1
No co-segregation data is available for this variant.
PP3
VCEP PP3 for non-canonical splice variants requires SpliceAI delta ≥ 0.2.
PP4
No tumor phenotype data (MSI status, IHC, or MMR protein expression) is available for patients carrying this variant.
Benign
BA1
VCEP BA1 Stand-Alone requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0022 (0.22%).
BS1
VCEP BS1_Strong requires gnomAD v4 grpmax filtering allele frequency ≥ 0.00022 (0.022%) and < 0.0022.
BS2
No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 without clinical manifestations of CMMRD.
BS3
VCEP BS3_Strong for intronic variants requires laboratory assays with NMD inhibition demonstrating no associated mRNA aberration.
BS4
No co-segregation data is available to assess lack of segregation with disease.
BP5
No tumor data (MSS/MSI status, IHC for MMR proteins, BRAF V600E, or MLH1 methylation) is available.
N/A · 11
PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 9.95616e-05; MAF= 0.00996%, 159/1597002 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000371147; MAF= 0.03711%, 23/61970 alleles, homozygotes = 0); grpmax FAF= 0.00020269.
v2.1
This variant is present in gnomAD v2.1 (AF= 5.87604e-05; MAF= 0.00588%, 16/272292 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000198636; MAF= 0.01986%, 6/30206 alleles, homozygotes = 0); grpmax FAF= 8.605e-05.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.01%
· 159 / 1,597,002
0 hom · FAF 0.02%
0 hom · FAF 0.02%
Remaining individuals 23 / 61,970 |
0.037% |
African/African American 22 / 73,358 |
0.03% |
South Asian 19 / 90,612 |
0.021% |
European (non-Finnish) 89 / 1,170,902 |
0.0076% |
Admixed American 4 / 59,764 |
0.0067% |
East Asian 2 / 44,646 |
0.0045% |
+ 4 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0059%
· 16 / 272,292
0 hom · FAF 0.0086%
0 hom · FAF 0.0086%
South Asian 6 / 30,206 |
0.02% |
Remaining individuals 1 / 7,024 |
0.014% |
African/African American 3 / 23,722 |
0.013% |
Admixed American 3 / 35,012 |
0.0086% |
European (non-Finnish) 3 / 124,648 |
0.0024% |
+ 3 not observed (Ashkenazi Jewish, East Asian, European (Finnish))
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 89502)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
Triaged references · 8 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
23788249 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
CLINVAR
25356965 ↗
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
CLINVAR
34043773 ↗
European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender.
CLINVAR
35802134 ↗
ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG).
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR