Classification rationale

BP7 VUS

MSH6 c.4001+32_4001+35dup

BP7 (Supporting): intronic variant at +32 to +35, beyond the VCEP's +7 boundary. Overall: VUS — a single supporting benign criterion reaches neither the Likely Benign (two benign criteria) nor Benign threshold, with zero pathogenic evidence.

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): the intronic duplication lies at +32 to +35, beyond the +7 boundary the VCEP BP7 rule requires.

Variant normalization: NM_000179.3:c.4001+32_4001+35dup (intronic duplication, +32 to +35 relative to exon 8, beyond +7)InSiGHT MSH6 VCEP v2.0 BP7 rule: intronic variant at or beyond -21/+7 qualifies for BP7_Supporting

cspec ↗

Assessed · not applied

Pathogenic

PVS1 Not met: the 4-bp duplication lies deep in intron 9 (+32 to +35), outside the canonical splice consensus, with no predicted protein-level consequence.

PS2 Not assessed: no de novo occurrence or parental testing data was available for this variant.

PS3 Not assessed: no functional assay, mRNA splicing, or allelic-expression data was available for this variant.

PM2 Not met: gnomAD v4 allele frequency of 9.96e-05 is ~5-fold above the <0.00002 extreme-rarity ceiling.

PM3 Not assessed: no second MSH6 variant or phase data existed to test trans co-occurrence.

PP1 Not assessed: no pedigree or co-segregation data was available for this variant.

PP3 Not met: SpliceAI max delta 0.12 is below the >=0.2 splice-defect threshold.

PP4 Not assessed: no MSI, immunohistochemistry, or tumor genome data was available for carriers.

Benign

BA1 Not met: gnomAD v4 Grpmax FAF 0.00020269 is ~10.8-fold below the 0.0022 BA1 threshold.

BS1 Not met: joint Grpmax FAF 0.00020269 falls just below the 0.00022 BS1 lower bound.

BS2 Not assessed: no trans co-occurrence with a pathogenic MSH6 variant or clinical phenotype data was available.

BS3 Not assessed: no mRNA aberration, functional, or allelic-expression assay data was available.

BS4 Not assessed: no non-segregation or meiosis data was available to test against segregation.

BP4 Not met: SpliceAI max delta 0.12 exceeds the <=0.1 BP4 threshold.

BP5 Not assessed: no MSS/IHC, BRAF V600E, or MLH1 methylation tumor 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

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

This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 89502)

ClinVar ↗

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

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