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LYFE SCIENCES
Project: HERA
NM_000249.4:c.1515T>C
p.Ser505=  ·  MLH1
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Classification rationale
1

The MLH1 c.1515T>C (p.Ser505=) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar predominantly as likely benign or benign.

clinvar ↗
2

This variant is present in gnomAD, including 5/1614044 alleles overall in v4.1 (AF 0.00000310) and 4/44880 East Asian alleles (AF 0.0000891), with a grpmax filtering allele frequency of 0.0000298 that is below the BA1 and BS1 thresholds.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In silico splicing analysis predicts no significant splice impact with a SpliceAI max delta score of 0.00, supporting BP4 for a synonymous variant; no MLH1 HCI prior entry for c.1515T>C was identified, and the available REVEL score was 0.343.

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= 1.98829e-05; MAF= 0.00199%, 5/251472 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000217462; MAF= 0.02175%, 4/18394 alleles, homozygotes = 0); grpmax FAF= 7.353e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 3.09781e-06; MAF= 0.00031%, 5/1614044 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 8.91266e-05; MAF= 0.00891%, 4/44880 alleles, homozygotes = 0); grpmax FAF= 2.978e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.343.
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.
ResidueS505
Hotspots ↗