Classification rationale

PM2 VUS

POLD1 c.376C>A

This variant is absent from large population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at moderate strength.¹ No additional pathogenic or benign criteria are met. In silico predictions are inconclusive (REVEL 0.461) and do not meet PP3 or BP4 thresholds. The variant has been reported once in ClinVar as a Variant of Uncertain Significance by a single clinical laboratory.² With only one moderate pathogenic criterion (PM2) and no supporting benign criteria, this variant is classified as a Variant of Uncertain Significance per ACMG/AMP 2015 guidelines.³

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗clinvar ↗

3 generic_acmg_combination_rules

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

POLD1 NM_002691.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 21 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 moderate Pathogenic

This variant is absent from large population databases, consistent with extremely low frequency in the general population and supporting potential pathogenicity.

Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes/genomes).Absent from gnomAD-Canada v1.0 (genomes).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS1 No pathogenic missense variant at the same amino acid position (Arg126) has been identified to support PS1.

PS2 No de novo observation with confirmed paternity and maternity has been reported for this variant.

PS3 No well-established in vitro or in vivo functional studies have been identified that demonstrate a damaging effect of this variant on POLD1 protein function.

PS4 No case-control or cohort studies demonstrate significantly increased prevalence of this variant in affected individuals versus controls.

PM1 The variant does not lie within a well-established mutational hotspot or critical functional domain.

PM6 No de novo observation has been reported for this variant.

PP1 No cosegregation data are available to evaluate segregation of this variant with disease in affected families.

PP2 No gene-specific missense constraint metric is available to support that POLD1 has a low rate of benign missense variation and that missense variants are a common disease mechanism.

PP3 Multiple in silico tools do not support a deleterious effect of this variant.

PP4 No detailed patient phenotype or family history data are available to assess specificity for POLD1-associated disease.

PP5 The variant is classified as Uncertain Significance in ClinVar by a single clinical laboratory (Ambry Genetics), not as pathogenic.

Benign

BA1 The variant is absent from gnomAD population databases; allele frequency does not exceed the 1% BA1 threshold.

BS1 The variant is absent from gnomAD population databases; allele frequency does not exceed the 0.3% BS1 threshold.

BS2 No observation of this variant in a healthy adult individual for a disorder with full penetrance has been reported.

BS3 No well-established in vitro or in vivo functional studies have been identified that demonstrate no damaging effect of this variant.

BS4 No segregation data in affected families are available to evaluate lack of cosegregation with disease.

BP1 Although POLD1 loss of function is a supported disease mechanism, there is no evidence that this specific missense variant has been observed in trans with a pathogenic truncating variant in POLD1.

BP2 No observation of this variant in trans with a pathogenic variant in POLD1, which is associated with autosomal dominant cancer predisposition.

BP4 Multiple lines of computational evidence do not convincingly suggest no impact on the gene product.

BP5 This variant has not been observed in a case with an alternative molecular basis for disease.

BP6 No reputable source reports this variant as benign.

N/A · 4 PVS1 · PM5 · BP3 · 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

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4668398)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.461. BayesDel score = 0.10049.

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

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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