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LYFE SCIENCES
Project: HERA
NM_000249.4:c.1682A>G
p.Tyr561Cys  ·  MLH1
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Classification rationale
1

The MLH1 c.1682A>G (p.Tyr561Cys; p.Y561C) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with uncertain significance submissions.

clinvar ↗
2

This variant is present at very low frequency in population databases, with gnomAD v4.1 total allele frequency 3.10936e-06 and grpmax filtering allele frequency 8e-07, which is below the MLH1 PM2_Supporting threshold of 0.00002.

cspec ↗ gnomad_v4 ↗ gnomad_v2 ↗
3

No variant-specific calibrated functional assay result for this variant was identified in the reviewed MMR functional assay materials, so functional evidence was not used to support or refute pathogenicity.

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, and available in silico evidence was insufficient to assign the MLH1 missense PP3 or BP4 rules without an HCI-prior value.

cspec ↗ spliceai ↗
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
—
—
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= 3.18512e-05; MAF= 0.00319%, 1/31396 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114784; MAF= 0.01148%, 1/8712 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 3.10936e-06; MAF= 0.00031%, 5/1608050 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33701e-05; MAF= 0.00134%, 1/74794 alleles, homozygotes = 0); grpmax FAF= 8e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (10 clinical laboratories) and as Uncertain Significance (1 clinical laboratory).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueY561
Hotspots ↗