NM_002691.4:c.1704G>A (p.Leu568=) is a synonymous variant in POLD1 exon 14 that is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (PM2_supporting).1 SpliceAI predicts no splice impact (max delta score = 0.00), and the variant is synonymous with no predicted amino acid change (BP7_supporting_benign).2 This variant is absent from ClinVar and has not been reported in COSMIC. No functional studies, segregation data, or variant-specific publications were identified.3 The available evidence includes one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP7). Under generic ACMG/AMP 2015 combination rules (PMID:25741868), this does not meet thresholds for Likely Pathogenic (requires ≥1 Moderate + ≥4 Supporting, or stronger), Likely Benign (requires ≥2 Supporting benign), or Benign (requires ≥2 Strong benign or BA1). The variant is classified as a Variant of Uncertain Significance (VUS).4
POLD1
Final classification
VUS
POLD1 c.1704G>A · p.Leu568=
POLD1
NM_002691.4:c.1704G>A (p.Leu568=) is a synonymous variant in POLD1 exon 14 that is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (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, BP7 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP7
VUS
POLD1 c.1704G>A
PM2 + BP7
→
VUS
Gene diagram
· NM_002691.4 · variants mapped to exon structure
POLD1
NM_002691.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 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, meeting the PM2 allele frequency threshold (<0.1%) for absence from population controls.
Absent from gnomAD v2.1 (0 alleles).Absent from gnomAD v4.1 (0 alleles).Absent from gnomAD-Canada v1.0 (0 alleles).
✓
BP7
supporting
Benign
NM_002691.4:c.1704G>A is a synonymous variant (p.Leu568=) for which SpliceAI predicts no splice impact (max delta score = 0.00, no acceptor gain/loss or donor gain/loss). Conservation data at this nucleotide position are not available, but the synonymous nature with no predicted splice alteration supports a benign interpretation.
Synonymous variant (p.Leu568=).SpliceAI max delta = 0.00all delta scores = 0.0 (DS_AG=0
Assessed · not applied
Pathogenic
PS2
No de novo occurrence data (with confirmed paternity and maternity) are available for this variant.
PS3
No well-established in vitro or in vivo functional studies are available for NM_002691.4:c.1704G>A.
PS4
No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals are available.
PM1
This variant does not reside in a statistically significant mutational hotspot (cancerhotspots.org) and no well-established POLD1 functional domain has been specifically implicated at this residue.
PM6
No de novo observation (without confirmation of paternity and maternity) has been reported for this variant.
PP1
No co-segregation data are available for this variant.
PP3
No computational evidence supports a deleterious effect.
PP4
No patient phenotype or family history data are available to assess specificity for a POLD1-associated disorder.
PP5
No reputable source has reported this variant as pathogenic.
Benign
BA1
This variant is absent from gnomAD; its population allele frequency does not exceed the 1% BA1 threshold.
BS1
This variant is absent from gnomAD; its population allele frequency does not exceed the 0.3% BS1 threshold for non-VCEP assessment.
BS2
No data are available regarding observation of this variant in healthy adult individuals for a fully penetrant disorder.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect are available for this variant.
BS4
No segregation data are available to assess lack of co-segregation with disease.
BP2
No data are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact.
BP5
No data are available regarding observation of this variant in a case with an alternate molecular basis for disease.
BP6
No reputable source has reported this variant as benign.
N/A · 6
PVS1 · PS1 · PM5 · PP2 · BP1 · BP3
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.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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