NM_002691.4:c.1704G>A

POLD1 · NP_002682.2:p.(Leu568=) · NM_002691.4

GRCh37: chr19:50910601 G>A · GRCh38: chr19:50407344 G>A

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

PM2 supporting BP7 supporting benign

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Leu568=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

SpliceAI predicts no splice impact (max delta score = 0.00), and the variant is synonymous with no predicted amino acid change (BP7_supporting_benign).

This variant is absent from ClinVar and has not been reported in COSMIC. No functional studies, segregation data, or variant-specific publications were identified.

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).

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.1704G>A is a synonymous variant (p.Leu568=). It does not fall into the null-variant buckets (nonsense, frameshift, canonical ±1,2 splice consensus) required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	PS1 requires the same amino acid change as a previously established pathogenic variant. This synonymous variant produces no amino acid change (p.Leu568=), so PS1 is structurally not applicable.
PS2	Not assessed	No de novo occurrence data (with confirmed paternity and maternity) are available for this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies are available for NM_002691.4:c.1704G>A.
PS4	Not assessed	No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals are available.
PS5	Not assessed	No reputable source has reported this variant as pathogenic where the underlying evidence is unavailable for independent evaluation.
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 applies to novel missense changes at a residue where a different pathogenic missense change has been reported. This synonymous variant produces no amino acid change (p.Leu568=) and therefore has no missense comparator context.	pm5_candidates
PM6	Not assessed	No de novo observation (without confirmation of paternity and maternity) has been reported for this variant.
PP1	Not assessed	No co-segregation data are available for this variant.
PP2	N/A	PP2 applies specifically to missense variants in genes with a low rate of benign missense variation. This variant is synonymous, not missense.
PP3	Not met	No computational evidence supports a deleterious effect. SpliceAI predicts no splice impact (max delta score = 0.00), and REVEL and BayesDel scores are not available for this synonymous variant.	spliceai
PP4	Not assessed	No patient phenotype or family history data are available to assess specificity for a POLD1-associated disorder.
PP5	Not assessed	No reputable source has reported this variant as pathogenic.
BA1	Not met	This variant is absent from gnomAD; its population allele frequency does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD; its population allele frequency does not exceed the 0.3% BS1 threshold for non-VCEP assessment.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation of this variant in healthy adult individuals for a fully penetrant disorder.
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no damaging effect are available for this variant.
BS4	Not assessed	No segregation data are available to assess lack of co-segregation with disease.
BP1	N/A	BP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. This variant is synonymous, not missense.
BP2	Not assessed	No data are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide substitution.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact. Only a single line (SpliceAI, max delta = 0.00) is available and applicable; REVEL and BayesDel are unavailable for this synonymous variant. BP7 is the more specific criterion for this evidence.	spliceai
BP5	Not assessed	No data are available regarding observation of this variant in a case with an alternate molecular basis for disease.
BP6	Not assessed	No reputable source has reported this variant as benign.
BP7	Met	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.	spliceai

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