Classification rationale

PM2 BP4 VUS

POLD1 c.2915C>T

The POLD1 c.2915C>T (p.Pro972Leu) variant has been reported in ClinVar as a variant of uncertain significance by one clinical laboratory.¹ This variant is absent from gnomAD v2.1 and has 0/1,552,088 alleles in gnomAD v4.1, which is below the 0.1% threshold used to support rarity.² Cancer Hotspots did not identify residue Pro972 as a statistically significant hotspot, which does not support application of PM1.³ Available computational evidence does not support a damaging or splice-altering effect, with REVEL 0.274, BayesDel -0.220831, and SpliceAI maximum delta score 0.01.⁴

PM2 + BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 hotspots ↗

4 revelbayesdelspliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_002691.4 · variants mapped to exon structure

POLD1 NM_002691.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 22 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 moderate review Pathogenic

This variant is absent from gnomAD v2.1 and observed at 0/1,552,088 alleles in gnomAD v4.1, which is below the 0.1% threshold used to support rarity in non-VCEP review. These data support that the variant is rare in population databases.

gnomAD v2.1: absent.gnomAD v4.1: 0/1552088 allelesAF 0.0

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting review Benign

Multiple computational results do not support a damaging or splice-altering effect. REVEL is 0.274, BayesDel is -0.220831, and SpliceAI shows a maximum delta score of 0.01, which is below a commonly used 0.20 threshold for significant splice impact.

REVEL 0.274.BayesDel -0.220831.SpliceAI max delta score 0.01.

spliceai ↗

Assessed · not applied · 12 not met · 10 not assessed

Pathogenic

PS1 No evidence was identified showing that this same amino acid change, p.Pro972Leu, has already been established as pathogenic through a different nucleotide change.

PS2 No confirmed de novo occurrence with established maternity and paternity was identified for this variant.

PS3 No well-established functional study for this exact variant was identified demonstrating a damaging effect on POLD1 function.

PS4 This variant has not been shown to be significantly enriched in affected individuals compared with controls.

PM1 Available hotspot evidence does not support that residue Pro972 lies in a well-established mutational hotspot or critical region without benign variation.

PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disorder context.

PM5 No evidence was identified showing a different pathogenic missense change at codon 972 that would support PM5.

PM6 No assumed de novo occurrence without confirmation of maternity and paternity was identified for this variant.

PP1 No segregation data were identified showing that this variant tracks with disease in affected relatives.

PP2 Available evidence for this case does not establish that POLD1 is a gene in which missense variation is a sufficiently common and well-supported disease mechanism to apply PP2 for this variant alone.

PP3 Available computational evidence does not support a deleterious effect.

PP4 No phenotype or family-history information was provided that is highly specific for a single genetic etiology and attributable to this variant.

PP5 No reputable-source pathogenic assertion was used without access to the underlying evidence.

Benign

BA1 Population frequency does not meet the benign stand-alone threshold.

BS1 Population frequency does not meet the benign strong threshold.

BS2 This variant was not observed in population databases in a manner that would support occurrence in healthy adults at a frequency expected for BS2.

BS3 No well-established functional study for this exact variant was identified showing normal POLD1 function.

BS4 No non-segregation data were identified showing that this variant fails to track with disease in a family.

BP1 Available evidence does not establish that POLD1 is a gene in which truncating variants are the primary disease mechanism such that a missense variant would favor BP1.

BP2 No phase information was identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in a way that would support BP2.

BP5 No alternate molecular diagnosis or other clearly explanatory variant data were provided to support BP5.

BP6 No reputable-source benign assertion was used without access to the underlying evidence.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1552088 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73292 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / 1,552,088
0 hom

Not observed in any ancestry group.

+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.274. BayesDel score = -0.220831.

SpliceAI ↗

Functional 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 ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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