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 ↗

Gene diagram · NM_000249.4 · variants mapped to exon structure

MLH1 NM_000249.4

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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