Classification rationale

BP7 VUS

MSH6 c.4001+32_4001+35dup

BP7 (Supporting): intronic variant at +32 to +35, beyond the VCEP -21/+7 boundary. Overall: VUS — one Benign Supporting criterion alone matches no combination rule; Likely Benign would require at least two Supporting criteria or a Strong plus a Supporting.

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): intronic variant at +32 to +35, beyond the VCEP -21/+7 boundary.

CSPEC InSiGHT MSH6 v2.0 BP7 rule: synonymous (silent) or intronic variant at or beyond -21/+7 (5'/3' exonic)Variant position: c.4001+32_4001+35dup = intron 9, +32 to +35 downstream of the exon (beyond +7)

cspec ↗

Assessed · not applied

Pathogenic

PVS1 Not met: this deep intronic duplication (intron 9, +32 to +35) creates no premature stop codon and matches no VCEP PVS1 tier.

PS2 Not assessed: no de novo occurrence or parental-testing data were available to score.

PS3 Not assessed: no calibrated functional assay, MMR function test, or mRNA expression data were available.

PM2 Not met: gnomAD v4.1 allele frequency 0.00996% (159/1,597,002 alleles) is about 5-fold above the <0.002% threshold.

PM3 Not assessed: no second MSH6 variant, phase testing, or CMMRD-consistent clinical features were available to score co-occurrence.

PP1 Not assessed: no pedigree or co-segregation data were available to compute a likelihood ratio.

PP3 Not met: SpliceAI max delta 0.12 is below the >=0.2 PP3 splice threshold, and the variant is not a missense.

PP4 Not assessed: no MSI status, MMR-immunohistochemistry results, or tumor-phenotype case reports were available.

Benign

BA1 Not met: gnomAD v4.1 grpmax FAF 0.0203% is an order of magnitude below the 0.22% BA1 threshold.

BS1 Not met: joint-callset grpmax FAF 0.0203% sits just below the 0.022% BS1 floor.

BS2 Not assessed: no phase-confirmed trans co-occurrence with a pathogenic MSH6 variant in a compatible patient was available.

BS3 Not assessed: no mRNA/cDNA assay or calibrated functional results were available for this intronic variant.

BS4 Not assessed: no pedigree-based non-segregation observations were available to compute a likelihood ratio.

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

BP5 Not assessed: no MSS, MMR-immunohistochemistry, or BRAF V600E/MLH1-methylation tumor data were 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

20301390 ↗ Lynch Syndrome. CLINVAR

23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome 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