Variant classification summary

NM_002691.4:c.3046C>T

POLD1 · NP_002682.2:p.(Arg1016Cys) · NM_002691.4

GRCh37: chr19:50919959 C>T · GRCh38: chr19:50416702 C>T

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Arg1016Cys)

gnomAD AF

5.83676513505626e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002691.4:c.3046C>T (p.Arg1016Cys) is a rare missense variant in the polymerase domain of POLD1, present at an extremely low frequency in gnomAD v4.1 (AF=0.00058%, 9/1,541,950 alleles; grpmax FAF=1.78e-05) and absent from gnomAD v2.1 (0/139,430 alleles), supporting PM2 at the supporting level.

2

Multiple in silico tools predict a benign effect: REVEL score 0.321 (below 0.5 threshold), BayesDel score -0.248952 (predicting benign), and SpliceAI max delta 0.00, collectively supporting BP4 at the supporting level.

3

This variant has been reported in ClinVar as Uncertain significance by three clinical laboratories (ClinVar Variation ID: 408104), and has been observed in COSMIC in one somatic cancer sample. No variant-specific functional studies, segregation data, or case-control data are available.

4

With PM2 (supporting) and BP4 (supporting) as the only applicable criteria, the evidence is conflicting and insufficient to classify this variant beyond Uncertain significance.

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	NM_002691.4:c.3046C>T is a missense substitution (p.Arg1016Cys), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The PVS1 decision framework (PMC6185798) does not apply to missense variants.	pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No evidence that the same amino acid change (p.Arg1016Cys) has been established as pathogenic via a different nucleotide change.
PS2	Not met	No de novo observation has been reported for NM_002691.4:c.3046C>T in any reviewed source.
PS3	Not assessed	No variant-specific functional studies were identified for NM_002691.4:c.3046C>T (p.Arg1016Cys). OncoKB notes gene-level context only. Full-text review of PMID:27149842 and PMID:29056344 did not mention this variant. No in vitro or in vivo functional data are available to adjudicate PS3.	oncokb PMID:27149842 PMID:29056344
PS4	Not met	No case-control or case-series data demonstrate a statistically significant enrichment of NM_002691.4:c.3046C>T in affected individuals compared to controls. PMID:25394175 is an ACMG practice guideline and does not report variant-specific prevalence.	PMID:25394175
PS5	N/A	PS5 is not a recognized criterion in the generic ACMG/AMP 2015 classification framework.
PM1	Not met	Residue p.Arg1016 is not located in a statistically significant mutational hotspot. No evidence was found that this residue lies within a critical functional domain devoid of benign variation.
PM2	Met	This variant is absent from gnomAD v2.1 (0/139,430 alleles) and is observed at an extremely low allele frequency in gnomAD v4.1 (AF=0.00058%, 9/1,541,950 alleles, grpmax FAF=1.78e-05), well below the 0.1% threshold for PM2. It is also absent from gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Unable to confirm classic same-residue PM5 semantics; no pathogenic or likely pathogenic comparator variants at codon 1016 were identified in ClinVar. pm5_candidates.json confirms no eligible candidates.	pm5_candidates
PM6	Not met	No de novo observation has been reported for NM_002691.4:c.3046C>T without confirmation of paternity and maternity.
PP1	Not met	No co-segregation data are available for this variant in affected families.
PP2	Not met	POLD1 has a non-trivial rate of benign missense variation in the general population. No gene-specific constraint data support a low rate of benign missense variation relative to disease-causing missense variants.
PP3	Not met	Multiple in silico tools predict a benign effect: REVEL score 0.321 (below typical pathogenicity threshold of 0.5), BayesDel score -0.248952 (predicting benign), SpliceAI max delta 0.00 (no splice impact). No in silico evidence supports a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history information is available to assess whether the clinical presentation is specific for POLD1-related disease.
PP5	Not met	ClinVar classification is 'Uncertain significance' (3 clinical laboratories, criteria provided, single submitter). No reputable source has classified NM_002691.4:c.3046C>T as pathogenic or likely pathogenic. PMID:25394175 is a practice guideline that does not report a classification for this variant; PMID:28492532 describes criteria methodology, not variant classification.	clinvar PMID:25394175
BA1	Not met	The maximum allele frequency in gnomAD v4.1 is 0.00058% (grpmax FAF=0.0018%), far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	The allele frequency in gnomAD v4.1 is 0.00058%, below the 0.3% BS1 threshold for a rare disease variant.	gnomad_v4
BS2	Not assessed	No data are available on observation of this variant in healthy adults to assess whether it is observed at high frequency in the context of a fully penetrant dominant disorder.
BS3	Not assessed	No variant-specific functional studies demonstrating no damaging effect on protein function have been published for p.Arg1016Cys.
BS4	Not met	No segregation data are available to demonstrate lack of segregation with disease in affected families.
BP1	N/A	POLD1 is not a gene in which only truncating variants cause disease. Missense variants in POLD1 (particularly in the exonuclease domain) are a recognized disease mechanism in polymerase proofreading-associated polyposis (PPAP).	pvs1_gene_context
BP2	Not assessed	No data are available on observation of this variant in trans with a known pathogenic POLD1 variant.
BP4	Met	Multiple in silico tools predict a benign effect: REVEL score 0.321 (below 0.5 threshold), BayesDel score -0.248952 (predicts benign), and SpliceAI delta 0.00 (no splicing impact). These scores collectively support a benign computational prediction.	revel bayesdel spliceai
BP5	Not met	No evidence is available that an alternate molecular basis for disease has been identified in cases carrying NM_002691.4:c.3046C>T.
BP6	Not met	ClinVar classification for this variant is 'Uncertain significance,' not benign or likely benign. No reputable source has classified this variant as benign.	clinvar
BP7	N/A	NM_002691.4:c.3046C>T is a missense variant (p.Arg1016Cys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.	spliceai
BP3	N/A	NM_002691.4:c.3046C>T is a substitution, not an in-frame deletion/insertion in a repetitive region.
PM3	N/A	POLD1-associated disease (PPAP) follows an autosomal dominant inheritance pattern; PM3 (in trans observation for recessive disorders) is not applicable.
PM4	N/A	NM_002691.4:c.3046C>T is a single-nucleotide missense substitution, not a protein-length-altering variant (in-frame deletion/insertion or stop-loss).

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