NM_001308632.1:c.319C>T

POLD1 · NP_001295561.1:p.(Pro107Ser) · NM_001308632.1

GRCh37: chr19:50905037 C>T · GRCh38: chr19:50401780 C>T

Gene: POLD1 Transcript: NM_001308632.1

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

POLD1

Transcript

NM_001308632.1

Protein

NP_001295561.1:p.(Pro107Ser)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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).

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.

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant (c.319C>T, p.Pro107Ser) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense substitutions.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence that a different nucleotide change at codon 107 resulting in the same Pro107Ser amino acid substitution has been classified as pathogenic.
PS2	Not met	No de novo occurrence data available for this variant. No parental testing or de novo confirmation reported in ClinVar submissions or literature.
PS3	Not met	No variant-specific functional studies identified. OncoKB reports unknown oncogenic effect with no curated functional evidence for this variant.	oncokb
PS4	Not met	No case-control or prevalence data establishing enrichment of this variant in affected individuals versus controls. ClinVar submissions represent isolated clinical observations without cohort-level statistics.	clinvar
PS5	Not met	No family segregation data available. No multigenerational pedigree or linkage analysis data reported.
PM1	Not met	Residue 107 is not within a recognized mutational hotspot or well-established critical functional domain without benign variation. Cancer Hotspots analysis found no statistically significant clustering at this residue.
PM2	Met	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).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Pro107) identified in ClinVar. Automated PM5 candidate harvesting found zero same-residue comparator variants.	pm5_candidates
PM6	Not met	No de novo variant reports identified in ClinVar or literature. No confirmed de novo occurrence with maternity/paternity testing.
PP1	Not met	No cosegregation data available. No family studies or pedigree analysis reported for this variant.
PP2	Not assessed	HCI Prior scores are not available for POLD1. Cannot assess the rate of benign missense variation in this gene relative to pathogenic missense variation. Insufficient data to determine whether missense variants are a common mechanism of disease in POLD1.
PP3	Not met	Multiple computational predictors do not support a deleterious effect. REVEL score is 0.015 (strongly benign-leaning; threshold >0.5 for pathogenic), BayesDel score is -0.70 (benign-leaning; threshold >0.0 for pathogenic), and SpliceAI predicts no splice impact (max delta score 0.01). These do not constitute multiple lines of computational evidence supporting pathogenicity.	revel bayesdel spliceai
PP4	Not met	No specific patient phenotype or family history data provided for assessment. Insufficient clinical information to evaluate phenotype specificity for a POLD1-associated condition.
PP5	Not met	No reputable source classifies this variant as pathogenic. ClinVar reports Uncertain significance from 2 clinical laboratories (Labcorp, GeneDx) and Likely benign from 1 laboratory (Ambry Genetics). The classification framework paper cited by Labcorp (PMID:28492532, Sherloc) is a methods reference, not a source of variant-specific evidence.	clinvar
BA1	Not met	Allele frequency is 0% in gnomAD v2.1, v4.1, and gnomAD-Canada, well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Allele frequency is 0% in gnomAD v2.1, v4.1, and gnomAD-Canada, below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data on observation of this variant in healthy adult controls. Absence from gnomAD is consistent with rarity but does not constitute observation in confirmed healthy individuals.
BS3	Not met	No well-established functional studies demonstrating no deleterious effect of this specific variant. Computational predictors suggest benign impact but do not constitute functional assay evidence.
BS4	Not met	No nonsegregation data available. No family studies demonstrating absence of cosegregation with disease.
BP1	Not met	POLD1 disease mechanism includes both loss-of-function and missense variants. Pathogenic missense variants in the exonuclease domain are well-established in polymerase proofreading-associated polyposis (PPAP). POLD1 is not a gene where only truncating variants cause disease.	pvs1_gene_context
BP2	Not met	No data on observation of this variant in trans with a known pathogenic POLD1 variant.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No alternate molecular basis for disease identified in cases carrying this variant.
BP6	Not met	No consensus benign classification from a reputable source. ClinVar reports mixed classifications: Uncertain significance (Labcorp, GeneDx) and Likely benign (Ambry Genetics). A single Likely benign classification without expert panel review does not meet the threshold for BP6.	clinvar
BP7	N/A	This is a missense variant (c.319C>T, p.Pro107Ser), not a synonymous/silent variant. BP7 only applies to synonymous variants without predicted splice impact.

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