Classification rationale

BP4BP7 Likely Benign

MSH6 c.2463A>C synonymous · exon 4

BP4 (Supporting): SpliceAI predicts no splicing impact (max delta 0.001, below the 0.1 threshold) for this synonymous variant. BP7 (Supporting): synonymous variant deep within the exon interior (1835 bp from the 5' splice boundary), with SpliceAI max delta 0.001 confirming no splice impact. Overall: Likely Benign, per InSiGHT MSH6 VCEP v2.0 Rule19 (>=2 Benign.Supporting criteria).

BP4 + BP7 → Likely Benign

Gene diagram · NM_000179.3 · variants mapped to exon structure

MSH6 NM_000179.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 13 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

BP4 supporting Benign

Met (supporting): SpliceAI max delta 0.001, well below the <=0.1 threshold indicating no splicing impact.

prefetch.json compact_evidence.spliceai evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).' Raw scores: DS_AG=0.001, DS_AL=0.0, DS_DG=0.0, DS_DL=0.0, max_delta_score=0.001.cspec BP4 rule (MSH6 VCEP v2.0): 'For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <=0.1 as per Walker et al 2023.' Variant qualifies as synonymous with delta well under threshold.

cspec ↗spliceai ↗

✓

BP7 supporting Benign

Met (supporting): synonymous variant deep in the exon interior (1835 bp from the 5' splice boundary) with SpliceAI max delta 0.001.

case_summary.json compact_evidence.normalization: protein consequence NP_000170.1:p.(Leu821=) confirms synonymous/silent change.prefetch.json compact_evidence.spliceai: max_delta_score=0.001 supports absence of cryptic splice disruption at this exonic position.cspec BP7 rule (MSH6 VCEP v2.0): 'A synonymous (silent) or intronic variant at or beyond -21/+7 (5'/3' exonic). Variants may satisfy both BP7 and BP4.' Exon boundary data (c.628-c.3172) places the variant far outside the -21/+7 zone.

cspec ↗spliceai ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

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

PS3 Not assessed: no functional assay or mRNA-based study results were available for this variant.

PM2 Not met: the highest ancestry-specific frequency (3.38e-05 in Ashkenazi Jewish) exceeds the <0.00002 cutoff despite a 6.20e-07 total frequency.

PM3 Not assessed: no co-occurring pathogenic MSH6 variant or CMMRD-consistent phenotype data were available.

PP1 Not assessed: no segregation or pedigree genotype/phenotype data were available.

PP3 Not met: SpliceAI max delta 0.001, far below the 0.2 PP3 threshold; the variant is also not missense.

PP4 Not assessed: no tumor MSI or MMR immunohistochemistry results were available.

Benign

BA1 Not met: highest ancestry-specific allele frequency 3.38e-05, far below the 0.0022 BA1 threshold.

BS1 Not met: highest ancestry-specific allele frequency 3.38e-05, more than six-fold below the 0.00022 lower bound.

BS2 Not assessed: no in-trans co-occurrence with a pathogenic MSH6 variant in an eligible patient was documented.

BS3 Not assessed: no NMD-inhibition mRNA assay or calibrated functional assay result was available.

BS4 Not assessed: no non-segregation observations or likelihood ratio data were available.

BP5 Not assessed: no tumor MSS, MMR IHC, BRAF V600E, or MLH1 methylation results were available.

N/A · 13 PVS1 · 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= 6.19593e-07; MAF= 0.00006%, 1/1613962 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37792e-05; MAF= 0.00338%, 1/29604 alleles, homozygotes = 0).

v2.1

This variant is present in gnomAD v2.1 (AF= 4.01065e-06; MAF= 0.00040%, 1/249336 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.96016e-05; MAF= 0.00996%, 1/10040 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,613,962
0 hom

Ashkenazi Jewish

1 / 29,604

0.0034%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, African/African American, European (non-Finnish))

gnomAD v2.1

0.0004% · 1 / 249,336
0 hom

Ashkenazi Jewish

1 / 10,040

0.01%

+ 7 not observed (African/African American, Admixed American, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

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 (3 clinical laboratories). (ClinVarID = 918700)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 3 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

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR