Classification rationale

BA1 Benign

MLH1 c.290A>G

The MLH1 c.290A>G (p.Tyr97Cys) variant has been observed once in somatic cancers in COSMIC and has been reported in ClinVar with conflicting germline interpretations, including uncertain significance, likely benign, and benign submissions.¹ This variant is present in gnomAD at a South Asian grpmax filtering allele frequency of 0.0015372 in v4.1, which is above the MLH1 VCEP BA1 threshold of 0.001; gnomAD v2.1 also shows elevated South Asian frequency with grpmax FAF 0.00153368.² SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01; REVEL is 0.603 and BayesDel is 0.230019, but no MLH1 VCEP HCI prior probability was identified to support PP3 or BP4 for this missense change.³

BA1 → Benign

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗cspec ↗

3 spliceai ↗revelbayesdelcspec ↗

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_000249.4 · variants mapped to exon structure

MLH1 NM_000249.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 16 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 · 1

Strength Supporting Moderate Strong Very strong

BA1 stand-alone review Benign

This variant is present in gnomAD v4.1 with a grpmax filtering allele frequency of 0.0015372 in the South Asian population, which is above the MLH1 VCEP BA1 threshold of 0.001. No founder pathogenic designation was identified in the available evidence.

gnomAD v4.1 joint grpmax FAF = 0.0015372Highest observed population = South Asian

gnomad_v4 ↗clinvar ↗cspec ↗

Assessed · not applied · 9 not met · 7 not assessed

Pathogenic

PVS1 This variant is a missense change, p.(Tyr97Cys), and does not fall into the default MLH1 null-variant categories for PVS1.

PS1 No previously established MLH1 pathogenic or likely pathogenic variant encoding the same Tyr97Cys amino acid change by a different nucleotide change was identified in the reviewed VCEP materials.

PS2 No de novo observation with the required parental confirmation and Lynch syndrome tumor context was identified for this variant.

PS3 No variant-specific calibrated functional assay result showing a damaging MLH1 effect was identified for this missense variant in the reviewed functional assay documentation or curated evidence sources.

PM2 This variant is not absent or extremely rare in gnomAD v4.1.

PM3 No evidence was identified that this variant occurs in trans with a pathogenic or likely pathogenic MLH1 variant in an individual meeting CMMRD-based scoring requirements.

PM5 No different MLH1 missense variant at Tyr97 established by this VCEP as pathogenic or likely pathogenic on the protein level was identified in the reviewed VCEP materials, so PM5 is not supported.

PP1 No segregation data were identified, so co-segregation with Lynch syndrome-associated disease could not be evaluated.

PP3 For MLH1 missense variants, PP3 requires an HCI prior probability of pathogenicity above 0.68.

PP4 No tumor microsatellite instability, mismatch repair immunohistochemistry, or MLH1 promoter methylation results were identified, so the Lynch syndrome tumor phenotype requirements for PP4 could not be evaluated.

Benign

BS1 The gnomAD v4.1 grpmax filtering allele frequency is 0.0015372, which is above the BS1 range of 0.0001 to less than 0.001 and instead falls into the BA1 range.

BS2 No confirmed in trans co-occurrence with a known pathogenic MLH1 variant in an appropriately phenotyped individual without evidence of CMMRD was identified.

BS3 No variant-specific functional study showing retained MLH1 function or normal RNA behavior was identified for this variant in the reviewed functional assay documentation or curated evidence sources.

BS4 No non-segregation data were identified, so lack of co-segregation with Lynch syndrome-associated disease could not be evaluated.

BP4 For MLH1 missense variants, BP4 requires an HCI prior probability of pathogenicity below 0.11.

BP5 No tumor evidence showing a molecular profile inconsistent with MLH1-related Lynch syndrome, such as MSS tumors, intact relevant MMR protein expression, or MLH1 methylation/BRAF findings, was identified.

N/A · 11 PS4 · PM1 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000107785; MAF= 0.01078%, 173/1605044 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00175975; MAF= 0.17598%, 160/90922 alleles, homozygotes = 0); grpmax FAF= 0.0015372.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000242661; MAF= 0.02427%, 61/251380 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00192735; MAF= 0.19273%, 59/30612 alleles, homozygotes = 0); grpmax FAF= 0.00153368.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.011% · 173 / 1,605,044
0 hom · FAF 0.15%

South Asian 160 / 90,922	0.18%
Middle Eastern 1 / 6,060	0.017%
Remaining individuals 10 / 62,190	0.016%
European (non-Finnish) 2 / 1,171,952	0.00017%

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

gnomAD v2.1

0.024% · 61 / 251,380
0 hom · FAF 0.15%

South Asian 59 / 30,612	0.19%
Remaining individuals 1 / 6,134	0.016%
European (non-Finnish) 1 / 113,674	0.00088%

+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Benign (2 clinical laboratories) and as likely benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.603. BayesDel score = 0.230019.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MLH1, a DNA mismatch repair protein, is recurrently altered by deletion and mutation in various cancer types.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV51621158, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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