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LYFE SCIENCES
Project: HERA
NM_000249.4:c.290A>G
p.Tyr97Cys  ·  MLH1
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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 ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
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 ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueY97
Hotspots ↗