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MSH6
Final classification
VUS
MSH6 c.4001+32_4001+35dup · p.?
MSH6

BP7 (Supporting): Deep intronic duplication at positions +32 to +35 of intron 9, well beyond the +7 boundary at which this benign criterion applies to intronic variants.

Gene
MSH6
Transcript
NM_000179.3
HGVS · transcript:coding
NM_000179.3:c.4001+32_4001+35dup
Consequence
N/A
GRCh38
chr2:47806677 A>ATAAC
GRCh37
chr2:48033816 A>ATAAC
Basis The variant was classified under the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specification for MSH6 v2.0, which takes precedence over the generic ACMG/AMP 2015 framework. The only criterion met is BP7 at supporting strength (benign); no pathogenic or likely pathogenic combination rule fires because no PVS1, PS, or PM criteria are met, and no benign combination rule fires because BA1 is not met, no strong benign criteria are met, and a single supporting benign criterion falls below the two supporting criteria a benign combination requires. With no combination rule satisfied, the variant remains a Variant of Uncertain Significance (VUS). ▾
The variant was classified under the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specification for MSH6 v2.0, which takes precedence over the generic ACMG/AMP 2015 framework. The only criterion met is BP7 at supporting strength (benign); no pathogenic or likely pathogenic combination rule fires because no PVS1, PS, or PM criteria are met, and no benign combination rule fires because BA1 is not met, no strong benign criteria are met, and a single supporting benign criterion falls below the two supporting criteria a benign combination requires. With no combination rule satisfied, the variant remains a Variant of Uncertain Significance (VUS).
Classification rationale
BP7 VUS
MSH6 c.4001+32_4001+35dup

BP7 (Supporting): Deep intronic duplication at positions +32 to +35 of intron 9, well beyond the +7 boundary at which this benign criterion applies to intronic variants. No pathogenic or benign combination rule is satisfied: the single supporting benign criterion (BP7) is below the two supporting criteria required for a benign combination, so the variant is classified as a Variant of Uncertain Significance (VUS).

BP7 → VUS
Gene diagram · NM_000179.3 · variants mapped to exon structure
MSH6 NM_000179.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 15 assessed
Applied · 1
Strength Supporting Moderate Strong Very strong
✓
BP7 supporting Benign
Met (Supporting). This variant lies in intron 9 at positions +32 to +35, well beyond the +7 boundary at which the expert panel's BP7 rule applies to intronic variants. The rule is purely positional and does not require a splice prediction, so the borderline SpliceAI score does not negate it.
Variant is an intronic variant at c.4001+32_4001+35dup (intron 9), i.e., 32-35 nucleotides into the intron, beyond the VCEP positional cutoff of +7.InSiGHT MSH6 VCEP v2.0 BP7 supporting rule: 'A synonymous (silent) or intronic variant at or beyond -21/+7 (5'/3' exonic). Variants may satisfy both BP7 and BP4.'
cspec ↗
Assessed · not applied
Pathogenic
PVS1 PVS1 (loss-of-function) is not met.
PS2 Not assessed: no proband or family information was available.
PS3 Not assessed: no functional evidence was available.
PM2 Not met.
PM3 Not assessed: no co-occurrence was observed.
PP1 Not assessed: no family data was available.
PP3 Not met.
PP4 Not assessed: no tumor phenotype data was available.
Benign
BA1 Not met.
BS1 Not met, though it is a borderline case flagged for review.
BS2 Not assessed: no qualifying case was available.
BS3 Not assessed: no functional evidence was available.
BS4 Not assessed: no family data was available.
BP4 Not met, by a narrow margin.
BP5 Not assessed: no tumor phenotype data was available.
N/A · 12 PS1 · PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
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%
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%
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
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 89502)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12).
SpliceAI ↗
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
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.
COSMIC ↗
Sources & reference links
8Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Triaged references · 8 PMIDs not cited in assessment
10537275 ↗ Germ-line msh6 mutations in colorectal cancer families. CLINVAR
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
34012068 ↗ ACMG SF v3.0 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
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