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LYFE SCIENCES
Project: HERA
NM_002691.4:c.2041del
p.Leu681SerfsTer13  ·  POLD1
ACMG/AMP
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Classification rationale
1

The POLD1 NM_002691.4:c.2041del (p.(Leu681SerfsTer13)) variant has been reported in ClinVar, where it is classified as uncertain significance by two clinical laboratories.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.00006% (1/1613242), which is well below the 0.1% rarity threshold used to support PM2.

gnomad_v2 ↗ gnomad_v4 ↗
3

No reviewed variant-specific functional studies were identified for this frameshift variant in the retrieved functional evidence sources.

oncokb ↗
4

This is a truncating frameshift variant for which the generic PVS1 framework is applicable, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.03.

pvs1_generic_framework ↗ 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
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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 v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 6.1987e-07; MAF= 0.00006%, 1/1613242 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47453e-07; MAF= 0.00008%, 1/1180006 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories).
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. POLD1, a DNA polymerase, is infrequently altered by mutation in cancer.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
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.
ResidueL681
Hotspots ↗