NM_002691.4:c.1681C>T

POLD1 · NP_002682.2:p.(Arg561Trp) · NM_002691.4

GRCh37: chr19:50910426 C>T · GRCh38: chr19:50407169 C>T

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

PM2 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Arg561Trp)

gnomAD AF

6.243514549261955e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 supporting: allele frequency 8.18e-06 in gnomAD v2.1 and 6.24e-07 in gnomAD v4.1 is far below the 0.0001 rarity cutoff, with zero homozygotes.

Final determination: Under the generic ACMG/AMP 2015 fallback rules a single supporting pathogenic criterion (PM2 supporting), with no moderate, strong, or very strong criterion and no benign evidence, satisfies no pathogenic, likely pathogenic, likely benign, or benign combination, so the variant remains VUS.

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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_002691.4:c.1681C>T in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Arg561Trp). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no pathogenic variant shares this p.Arg561Trp change, and c.1681C>T is the only substitution at codon 561 (CGG) able to encode tryptophan.	clinvar PMID:25741868
PS2	Not assessed	Not assessed: no proband or parental-testing data exists in this case, so a de novo occurrence with confirmed parentage cannot be established.	clinvar PMID:25741868
PS3	Not assessed	Not assessed: no functional assay data for POLD1 p.Arg561W were identified, so the PS3 requirement for a well-established damaging-effect study is unmet.	oncokb clinvar PMID:25741868
PS4	Not met	Not met: no case-control or case-series data exist for c.1681C>T, so no odds ratio could be computed against the PS4 enrichment requirement.	clinvar PMID:25741868
PM1	Not met	Not met: CancerHotspots found no hotspot at R561, which lies outside the POLD1 exonuclease domain (residues ~243-477) where pathogenic missense variants cluster.	PMID:25741868 clinvar pvs1_gene_context
PM2	Met	Met at supporting strength: total allele frequency 8.18e-06 in gnomAD v2.1 sits below the 0.0001 PM2 threshold, with zero homozygotes and absence from gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no phase, zygosity or second-allele data exists for this variant, so a trans configuration with a pathogenic POLD1 allele cannot be established.	clinvar PMID:25741868
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_002691.4:c.1681C>T in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Arg561Trp). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: the only same-residue comparators, p.Arg561Gln and p.Arg561Gly, are both classified Uncertain significance in ClinVar, so no pathogenic comparator exists.	clinvar pm5_candidates
PM6	Not assessed	Not assessed: no proband or parental data is present in this case, so an assumed de novo event cannot be asserted for this variant.	clinvar PMID:25741868
PP1	Not assessed	Not assessed: no pedigree or affected-relative genotype data exists in this case, so co-segregation (zero informative meioses) cannot be evaluated.	clinvar PMID:25741868
PP2	Not met	Not met: POLD1 is not significantly missense-constrained in gnomAD (missense Z 2.46 v2.1.1 and 2.75 v4.1, both below 3.09), so a low rate of benign missense variation is unproven.	gnomad_v4 gnomad_v2 clinvar pvs1_gene_context PMID:25741868
PP3	Not met	Not met: REVEL 0.386 is below the 0.644 missense PP3 supporting cutoff.	revel PMID:25741868
PP4	Not assessed	Not assessed: no proband phenotype or family history is available, and ClinVar condition labels are gene-level rather than patient-specific.	clinvar
PP5	Not met	Not met: ClinVar VCV000469212 is Uncertain significance from two single-submitter clinical laboratories, with no expert-panel classification.	clinvar PMID:25741868
BA1	Not met	Not met: the highest ancestry-specific allele frequency, 2.94e-05 (gnomAD v2.1 Admixed American), is far below the 0.05 BA1 stand-alone threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the maximum observed allele frequency, 2.94e-05 (gnomAD v2.1 Admixed American), is roughly 340-fold below the 0.01 BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: zero homozygotes in gnomAD v2.1/v4.1, and POLD1 cancer predisposition is adult-onset with incomplete penetrance, not a fully penetrant early-onset disorder.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional study of POLD1 p.Arg561W was found, so absence of a damaging effect cannot be demonstrated for BS3.	oncokb clinvar PMID:25741868
BS4	Not assessed	Not assessed: no family segregation data exists in this case, so non-segregation of this variant with disease cannot be demonstrated.	clinvar PMID:25741868
BP1	Not met	Not met: POLD1 pathogenic missense variants are established (ClinVar Pathogenic/Likely pathogenic p.Leu474Pro and p.Ser478Asn), so disease is not caused by truncating variants alone.	clinvar pvs1_gene_context
BP2	Not assessed	Not assessed: this case records no cis/trans phase or second POLD1 variant, so neither the dominant-trans nor the cis limb of BP2 can be evaluated.	clinvar PMID:25741868
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_002691.4:c.1681C>T in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Arg561Trp). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.386 is above the 0.29 BP4 supporting cutoff, a gray-zone result.	revel PMID:25741868
BP5	Not assessed	Not assessed: no case carrying c.1681C>T is described, so no alternate molecular basis for disease could be documented.
BP6	Not met	Not met: no expert-panel Benign or Likely benign classification exists; ClinVar VCV000469212 is Uncertain significance from two clinical laboratories.	clinvar PMID:25741868
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002691.4:c.1681C>T in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Arg561Trp). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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