Classification rationale

BS1BP4 Likely Benign

MLH3 c.3280+14A>T unknown · exon 2i

Likely Benign: BS1 (strong) - gnomAD East Asian allele frequency 1.12% (223/19,948 alleles) and grpmax filtering AF 1.01% exceed the 0.01 threshold expected for MLH3-related disease. Likely Benign: BP4 (supporting) - SpliceAI max delta 0.005 indicates no splice-altering effect, far below the 0.2 supporting cutoff. Not pathogenic: no pathogenic or likely pathogenic criterion is met, and no variant-level functional, segregation, de novo, or case-enrichment evidence is available.

BS1 + BP4 → Likely Benign

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_001040108.2 · variants mapped to exon structure

MLH3 NM_001040108.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 18 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

BS1 strong review Benign

Met at strong: East Asian AF 1.12% (223/19,948 alleles, gnomAD v2.1) and v2.1 grpmax FAF 1.01% exceed the 0.01 BS1 threshold.

gnomAD v2.1 (all-comers, default source): East Asian AF 0.011179065570483256 (223/19,948 alleles, 3 homozygotes; EAS exome 209/18,392, EAS genome 14/1,556); grpmax FAF 0.010101569999999992 (exome), which is also the variant's overall grpmax FAF; total AF 0.0007959586526011929 (225/282,678, 3 homozygotes).gnomAD v2.1 non-cancer exome subset (corroboration): East Asian 221/19,246 (AF 0.01148290553881326, 3 homozygotes); grpmax FAF 0.010396179999999986; total exome AF 0.0008783932161016233 (208/236,796, 3 homozygotes). Concordant with, and slightly above, the all-comers figures, so the frequency excess is not attributable to cancer-cohort inclusion.gnomAD v4.1 (all-comers): East Asian 332/44,880 (AF 0.007397504456327986, 2 homozygotes); joint grpmax FAF 0.00674173; total AF 0.0002193343882863045 (354/1,613,974, 2 homozygotes). Below the 1% generic default - the source of the discordance flagged for review.

gnomad_v2 ↗gnomad_v4 ↗PMID:25741868 ↗PMID:34043773 ↗

BP4 supporting Benign

Met at supporting: SpliceAI max delta 0.005, at or below the <=0.1 BP4 threshold.

SpliceAI Lookup for NM_001040108.2:c.3280+14A>T returned max delta score 0.005 (DS_AG 0.005, DS_AL 0.000, DS_DG 0.002, DS_DL 0.003; DP_DG 14 for the only gain predicted), i.e. no predicted splice impact.Applied threshold: SpliceAI BP4 supporting <= 0.1 (SpliceAI recommended cutoff, Jaganathan et al. 2019, Cell, PMID:30661751); the generic framework defines no moderate or strong benign tier for SpliceAI, so strength is supporting.Scope: the variant is intronic (14 nt into the intron 3' of c.3280) and outside the canonical +/-1,2 splice sites, so the intronic/splice-region SpliceAI path is the applicable predictor path and no REVEL missense path applies (REVEL score null, not found).

spliceai ↗PMID:25741868 ↗

Assessed · not applied · 8 not met · 10 not assessed

Pathogenic

PS2 Not assessed: no proband or parental genotype data was available, so a confirmed de novo occurrence could not be evaluated.

PS3 Not assessed: no functional assay of MLH3 c.3280+14A>T exists; the only nearby data, SpliceAI max delta 0.005, is in-silico and not assay evidence.

PS4 Not met: no case-control or case-enrichment data exist for c.3280+14A>T, and no MLH3 VCEP defines a numeric PS4 threshold.

PM1 Not met: c.3280+14A>T is intronic (p.?) and outside every MLH3 critical-domain entry, with the VCEP domain table empty and SpliceAI max delta 0.005 excluding a splice hotspot.

PM2 Not met: gnomAD v2.1 AF 0.0796% (225/282,678 alleles, 3 homozygotes) is about 8-fold above the 0.0001 PM2 threshold.

PM3 Not assessed: no affected-proband genotype, second MLH3 variant, or phase data exists to show c.3280+14A>T in trans with a pathogenic allele.

PM6 Not assessed: no proband-level clinical or genotype record exists, so an assumed de novo occurrence could not be evaluated.

PP1 Not assessed: no pedigree or affected-relative genotypes exist, so co-segregation with disease could not be evaluated across any meioses.

PP3 Not met: SpliceAI max delta 0.005, far below the >=0.2 PP3 supporting cutoff.

PP4 Not assessed: no proband phenotype or family history is available in this case, so PP4 specificity cannot be evaluated.

PP5 Not met: none of the four ClinVar submitters is an expert panel; zero expert-panel classifications exist for c.3280+14A>T.

Benign

BA1 Not met: the highest credible population frequency is 1.12% (East Asian, gnomAD v2.1), about 4.5-fold below the 5% BA1 threshold.

BS2 Not met: MLH3-related disease is adult-onset and incompletely penetrant, not the fully penetrant early-onset disorder BS2 requires, despite 3 homozygotes in gnomAD.

BS3 Not assessed: no functional assay reports either effect for MLH3 c.3280+14A>T; SpliceAI delta 0.005 is in-silico, not assay, evidence.

BS4 Not assessed: no affected relative genotypes exist, so lack of co-segregation in a family could not be evaluated.

BP2 Not assessed: no pathogenic comparator variant and no cis/trans phase determination exist, so neither BP2 clause can be evaluated for c.3280+14A>T.

BP5 Not assessed: no case-level data on an alternate molecular basis exists, and no MLH3 VCEP defines a numeric BP5 threshold.

BP6 Not met: no ClinVar expert-panel Benign or Likely benign classification exists for c.3280+14A>T; all four submitters are ordinary laboratories.

N/A · 8 PVS1 · PS1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000219334; MAF= 0.02193%, 354/1613974 alleles, homozygotes = 2) and has highest observed frequency in the East Asian population (AF= 0.0073975; MAF= 0.73975%, 332/44880 alleles, homozygotes = 2); grpmax FAF= 0.00674173.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000795959; MAF= 0.07960%, 225/282678 alleles, homozygotes = 3) and has highest observed frequency in the East Asian population (AF= 0.0111791; MAF= 1.11791%, 223/19948 alleles, homozygotes = 3); grpmax FAF= 0.0101016.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.022% · 354 / 1,613,974
2 hom · FAF 0.67%

East Asian 332 / 44,880	0.74% 2 hom
Remaining individuals 14 / 62,510	0.022%
Middle Eastern 1 / 6,058	0.017%
European (non-Finnish) 7 / 1,179,820	0.00059%

+ 6 not observed (Admixed American, European (Finnish), Amish, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.08% · 225 / 282,678
3 hom · FAF 1%

East Asian 223 / 19,948	1.1% 3 hom
Remaining individuals 2 / 7,222	0.028%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), 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 Benign (3 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 314378)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV53158903, n = 1 times).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 4 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

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.

34043773 ↗ European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender.

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 4 PMIDs not cited in assessment

20301390 ↗ Lynch Syndrome. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR

26389505 ↗ Genetics of Colorectal Cancer (PDQ®): Health Professional Version. CLINVAR

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

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