NM_000179.3:c.4002-26_4002-25insCT is present in gnomAD v4.1 at a grpmax filtering allele frequency of 2.41% in the East Asian population, exceeding the InSiGHT MSH6 VCEP BA1 stand-alone benign threshold of 0.22%. This population frequency is incompatible with a pathogenic role in Lynch syndrome.1 SpliceAI predicts no splicing impact (max delta = 0.02), meeting the VCEP BP4_Supporting criterion for intronic variants.2 The variant is located at intronic positions -26/-25, satisfying the VCEP BP7_Supporting criterion for intronic variants at or beyond -21/+7.3 No pathogenic evidence criteria are met: PVS1 is not applicable (deep intronic, no null-allele evidence); PM2 is not met (gnomAD v4.1 AF = 0.185%); PP3 is not met (SpliceAI delta 0.02 < 0.2); and no functional, segregation, de novo, or tumor phenotype data support pathogenicity.4
MSH6
Final classification
Benign
MSH6 c.4002-26_4002-25insCT · p.?
MSH6
NM_000179.3:c.4002-26_4002-25insCT is present in gnomAD v4.1 at a grpmax filtering allele frequency of 2.41% in the East Asian population, exceeding the InSiGHT MSH6 VCEP BA1 stand-alone benign threshold of 0.22%. This population frequency is incompatible with a pathogenic role in Lynch syndrome.
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.4002-26_4002-25insCT
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 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
Population frequency
Overall AF
186 / 100,732
0.18%
Highest · East Asian
2.9%
Homozygotes
0
grpmax FAF
2.4%
Allele frequency by ancestry — gnomAD v4.1
observed in 7 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| East Asian | 105 / 3,682 | 2.9% | 0 |
| Middle Eastern | 2 / 292 | 0.68% | 0 |
| South Asian | 14 / 5,426 | 0.26% | 0 |
| Admixed American | 9 / 8,196 | 0.11% | 0 |
| African/African American | 9 / 10,398 | 0.087% | 0 |
| European (non-Finnish) | 31 / 62,992 | 0.049% | 0 |
| European (Finnish) | 1 / 4,598 | 0.022% | 0 |
| Amish | 0 / 308 | — | — |
| Ashkenazi Jewish | 0 / 1,782 | — | — |
“
This variant is present in gnomAD v4.1 (AF= 0.00184648; MAF= 0.18465%, 186/100732 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.0285171; MAF= 2.85171%, 105/3682 alleles, homozygotes = 0); grpmax FAF= 0.0240982.
Overall AF
112 / 165,624
0.068%
Highest · East Asian
0.68%
Homozygotes
0
grpmax FAF
0.64%
Allele frequency by ancestry — gnomAD v2.1
observed in 7 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| East Asian | 74 / 10,808 | 0.68% | 0 |
| African/African American | 17 / 13,474 | 0.13% | 0 |
| Remaining individuals | 2 / 4,378 | 0.046% | 0 |
| Admixed American | 9 / 21,612 | 0.042% | 0 |
| South Asian | 5 / 19,860 | 0.025% | 0 |
| European (Finnish) | 1 / 11,954 | 0.0084% | 0 |
| European (non-Finnish) | 4 / 76,120 | 0.0053% | 0 |
| Ashkenazi Jewish | 0 / 7,418 | — | — |
“
This variant is present in gnomAD v2.1 (AF= 0.00067623; MAF= 0.06762%, 112/165624 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00684678; MAF= 0.68468%, 74/10808 alleles, homozygotes = 0); grpmax FAF= 0.00636889.
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Benign (1 clinical laboratory). (ClinVarID = 1280853)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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