NM_001308632.1:c.319C>T (p.Pro107Ser) is a missense variant in exon 3 of POLD1. It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_supporting).1 Multiple in silico predictors suggest a benign effect: REVEL score 0.015, BayesDel score -0.70, and SpliceAI max delta 0.01 predict no deleterious impact on protein function or splicing (BP4_supporting).2 This variant has been reported in ClinVar (Variation ID 848162) as a Variant of Uncertain Significance by two clinical laboratories (Labcorp, GeneDx) and as Likely benign by one laboratory (Ambry Genetics). No expert panel review has been performed.3 No variant-specific functional studies, segregation data, case-control analyses, or de novo reports were identified. OncoKB reports unknown oncogenic effect with no curated functional evidence.4 Under generic ACMG/AMP 2015 combination rules, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in an overall classification of Variant of Uncertain Significance (VUS).5
POLD1
Final classification
VUS
POLD1 c.319C>T · p.Pro107Ser
POLD1
NM_001308632.1:c.319C>T (p.Pro107Ser) is a missense variant in exon 3 of POLD1. It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_supporting).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
POLD1 c.319C>T
PM2 + BP4
→
VUS
Gene diagram
· NM_001308632.1 · variants mapped to exon structure
POLD1
NM_001308632.1
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with rarity. Meets PM2 at supporting level under generic ACMG/AMP (allele frequency below 0.1% threshold).
Absent from gnomAD v2.1 (0 alleles).Absent from gnomAD v4.1 (0 alleles).Absent from gnomAD-Canada v1.0 (0 alleles).
✓
BP4
supporting
Benign
Multiple lines of computational evidence predict no deleterious effect. REVEL score is 0.015 (strongly benign-leaning; well below typical pathogenic threshold of 0.5), BayesDel score is -0.70 (benign-leaning), and SpliceAI predicts no splice impact (max delta score 0.01). GeneDx clinical submission also noted that in silico analysis supports no alteration of protein structure/function.
REVEL 0.015 (strongly benign-leaning).BayesDel -0.70 (benign-leaning).SpliceAI max delta 0.01 (no predicted splice impact).
Assessed · not applied
Pathogenic
PS1
No evidence that a different nucleotide change at codon 107 resulting in the same Pro107Ser amino acid substitution has been classified as pathogenic.
PS2
No de novo occurrence data available for this variant.
PS3
No variant-specific functional studies identified.
PS4
No case-control or prevalence data establishing enrichment of this variant in affected individuals versus controls.
PM1
Residue 107 is not within a recognized mutational hotspot or well-established critical functional domain without benign variation.
PM5
No pathogenic missense variant at the same amino acid residue (Pro107) identified in ClinVar.
PM6
No de novo variant reports identified in ClinVar or literature.
PP1
No cosegregation data available.
PP2
HCI Prior scores are not available for POLD1.
PP3
Multiple computational predictors do not support a deleterious effect.
PP4
No specific patient phenotype or family history data provided for assessment.
PP5
No reputable source classifies this variant as pathogenic.
Benign
BA1
Allele frequency is 0% in gnomAD v2.1, v4.1, and gnomAD-Canada, well below the 1% BA1 threshold.
BS1
Allele frequency is 0% in gnomAD v2.1, v4.1, and gnomAD-Canada, below the 0.3% BS1 threshold.
BS2
No data on observation of this variant in healthy adult controls.
BS3
No well-established functional studies demonstrating no deleterious effect of this specific variant.
BS4
No nonsegregation data available.
BP1
POLD1 disease mechanism includes both loss-of-function and missense variants.
BP2
No data on observation of this variant in trans with a known pathogenic POLD1 variant.
BP5
No alternate molecular basis for disease identified in cases carrying this variant.
BP6
No consensus benign classification from a reputable source.
N/A · 2
PVS1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 848162)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.015. BayesDel score = -0.699995.
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.
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.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR