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LYFE SCIENCES
Project: HERA
NM_000249.4:c.1039-6dup
p.?  ·  MLH1
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Classification rationale
1

The MLH1 c.1039-6dup (p.?) variant has been reported in ClinVar as benign by 5 clinical laboratories and likely benign by 4 clinical laboratories.

clinvar ↗
2

This variant is present in population databases; in gnomAD v4.1 the overall allele frequency is 0.000530357 and the grpmax filtering allele frequency is 0.00117106, which is above the MLH1 VCEP BA1 threshold of 0.001.

gnomad_v4 ↗ cspec ↗
3

SpliceAI predicts no significant splice effect, with a maximum delta score of 0.01, which is below the BP4 no-impact threshold of 0.1 and below the PP3 splice-defect threshold of 0.2 in the MLH1 VCEP rules.

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= 0.000263237; MAF= 0.02632%, 37/140558 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000807103; MAF= 0.08071%, 10/12390 alleles, homozygotes = 0); grpmax FAF= 0.00082842.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0.000530357; MAF= 0.05304%, 653/1231246 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00142622; MAF= 0.14262%, 78/54690 alleles, homozygotes = 0); grpmax FAF= 0.00117106.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Benign (5 clinical laboratories) and as Likely benign (4 clinical laboratories).
ClinVar ↗
03
Functional
No functional summary recorded.
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 has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
06
Cancer hotspots
No cancer hotspot summary recorded.