Classification rationale

PM2 VUS

POLD1 c.2953C>T

The POLD1 c.2953C>T (p.Arg985Trp) variant has been reported in ClinVar as a variant of uncertain significance by five clinical laboratories.¹ This variant is present at very low frequency in population databases, with gnomAD v2.1 AF 1.07182e-05 (2/186598) and gnomAD v4.1 AF 5.15439e-06 (8/1552074), both below the 0.1% PM2 threshold.² Computational evidence is conflicting: SpliceAI predicts possible splice impact with a max delta score of 0.59, whereas REVEL is low at 0.126 and BayesDel is -0.414351, so PP3 and BP4 are not applied.³

PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗revelbayesdel

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

POLD1 NM_002691.4

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.15439e-06; MAF= 0.00052%, 8/1552074 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.554e-05; MAF= 0.00355%, 3/84412 alleles, homozygotes = 0); grpmax FAF= 9.44e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.07182e-05; MAF= 0.00107%, 2/186598 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.86441e-05; MAF= 0.00586%, 1/17052 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00052% · 8 / 1,552,074
0 hom · FAF 0.00094%

South Asian 3 / 84,412	0.0036%
African/African American 1 / 73,290	0.0014%
European (non-Finnish) 4 / 1,149,942	0.00035%

+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.0011% · 2 / 186,598
0 hom

African/African American 1 / 17,052	0.0059%
South Asian 1 / 23,132	0.0043%

+ 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.59). REVEL score = 0.126. BayesDel score = -0.414351.

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