BA1 is met at stand-alone strength: gnomAD v4.1 grpmax filtering allele frequency is 0.027 (2.70%), far exceeding the VCEP threshold of ≥0.0022 (0.22%). The variant is observed in 6 homozygotes in v4.1 and 2 homozygotes in v2.1, and is not a known founder pathogenic variant.1 BP7 is met at supporting benign strength: the variant is an intronic duplication at positions -26 to -28 relative to exon 10, which is beyond the VCEP BP7 threshold of -21.2 BP4 is met at supporting benign strength: SpliceAI predicts no splicing impact (max delta score = 0.00), meeting the VCEP BP4_Supporting threshold of ≤0.1 for intronic variants.3 Per the InSiGHT MSH6 VCEP v2.0.0 combination rules, BA1 stand-alone alone is sufficient for a Benign classification (Rule 17).4
MSH6
Final classification
Benign
MSH6 c.4002-28_4002-26dup · p.?
MSH6
BA1 is met at stand-alone strength: gnomAD v4.1 grpmax filtering allele frequency is 0.027 (2.70%), far exceeding the VCEP threshold of ≥0.0022 (0.22%). The variant is observed in 6 homozygotes in v4.1 and 2 homozygotes in v2.1, and is not a known founder pathogenic variant.
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 2.0.0 v2.0.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BP4 supporting benign, BP7 supporting benign; maps to Benign.
Classification rationale
BA1BP4BP7
Benign
MSH6 c.4002-28_4002-26dup
BA1 + BP4 + BP7
→
Benign
Gene diagram
· NM_000179.3 · variants mapped to exon structure
MSH6
NM_000179.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 12 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
gnomAD v4.1 grpmax filtering allele frequency is 0.027 (2.70%), far exceeding the VCEP BA1 stand-alone threshold of ≥0.0022 (0.22%). The variant is observed in 6 homozygotes in v4.1 and 2 homozygotes in v2.1. Highest frequency in the East Asian population (2.83% in v4, 3.14% in v2). No evidence this is a founder pathogenic variant.
gnomAD v4.1 grpmax FAF = 0.027 (2.70%)gnomAD v2.1 grpmax FAF = 0.057 (5.66%)gnomAD v4.1: 6 homozygotes
✓
BP4
supporting
Benign
SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00), meeting the VCEP BP4_Supporting threshold of ≤0.1 per Walker et al. 2023.
SpliceAI max delta = 0.00VCEP BP4_Supporting threshold: SpliceAI delta ≤ 0.1 for intronic variants
✓
BP7
supporting
Benign
Intronic duplication located at positions -26 and -28 relative to exon 10, which is at or beyond the VCEP BP7 threshold of -21. SpliceAI predicts no splicing impact (max delta = 0.00).
Variant position: c.4002-28_4002-26 (intronicbeyond -21 from exon boundary)SpliceAI max delta = 0.00
Assessed · not applied
Pathogenic
PVS1
Intronic duplication at c.4002-28_4002-26 (26-28 nucleotides upstream of exon 10 in MSH6 intron 9).
PS2
No de novo observations have been reported for this variant in any database or literature.
PS3
No calibrated functional assay data available for this variant.
PM2
Variant is present in gnomAD v4.1 at an allele frequency of 0.134% (1883/1403604 alleles, 6 homozygotes), far exceeding the VCEP PM2_Supporting threshold of <0.002% (<1 in 50,000 alleles).
PP1
No co-segregation data available for this variant.
PP3
SpliceAI predicts no splicing impact (max delta score = 0.00), below the VCEP PP3_Supporting threshold of ≥0.2 for non-canonical splice variants.
PP4
No tumor phenotype data (MSI status, IHC for MMR protein expression) have been reported for patients carrying this variant.
Benign
BS1
gnomAD v4.1 grpmax FAF is 0.027 (2.70%), which exceeds the VCEP BS1 upper bound of <0.0022 (0.22%).
BS2
No data demonstrating co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 without CMMRD features.
BS3
No laboratory functional assay data available demonstrating no splicing aberration or proficient MMR function.
BS4
No segregation data available to evaluate lack of co-segregation with disease.
BP5
No tumor phenotype data (MSS status, MMR IHC, BRAF V600E, MLH1 methylation) available for patients carrying this variant.
N/A · 12
PS1 · 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= 0.00134155; MAF= 0.13415%, 1883/1403604 alleles, homozygotes = 6) and has highest observed frequency in the East Asian population (AF= 0.0283305; MAF= 2.83305%, 1159/40910 alleles, homozygotes = 5); grpmax FAF= 0.0269749.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00252012; MAF= 0.25201%, 570/226180 alleles, homozygotes = 2) and has highest observed frequency in the East Asian population (AF= 0.0313601; MAF= 3.13601%, 445/14190 alleles, homozygotes = 2); grpmax FAF= 0.0565538.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.13%
· 1883 / 1,403,604
6 hom · FAF 2.7%
6 hom · FAF 2.7%
East Asian 1159 / 40,910 |
2.8% 5 hom |
African/African American 143 / 59,072 |
0.24% 1 hom |
Remaining individuals 127 / 55,562 |
0.23% |
Admixed American 83 / 55,138 |
0.15% |
South Asian 81 / 83,322 |
0.097% |
Middle Eastern 4 / 5,610 |
0.071% |
European (non-Finnish) 283 / 1,016,204 |
0.028% |
European (Finnish) 3 / 58,906 |
0.0051% |
+ 2 not observed (Amish, Ashkenazi Jewish)
gnomAD v2.1
0.25%
· 570 / 226,180
2 hom · FAF 5.7%
2 hom · FAF 5.7%
East Asian 445 / 14,190 |
3.1% 2 hom |
African/African American 57 / 18,028 |
0.32% |
Remaining individuals 12 / 5,958 |
0.2% |
Admixed American 27 / 30,310 |
0.089% |
South Asian 12 / 25,840 |
0.046% |
European (non-Finnish) 16 / 102,806 |
0.016% |
European (Finnish) 1 / 20,050 |
0.005% |
+ 1 not observed (Ashkenazi Jewish)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Benign (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 926536)
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 · 2 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
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR