NM_002691.4:c.376C>A

POLD1 · NP_002682.2:p.(Arg126Ser) · NM_002691.4

GRCh37: chr19:50905094 C>A · GRCh38: chr19:50401837 C>A

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

PM2 moderate

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Arg126Ser)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant is absent from large population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at moderate strength.

No additional pathogenic or benign criteria are met. In silico predictions are inconclusive (REVEL 0.461) and do not meet PP3 or BP4 thresholds. The variant has been reported once in ClinVar as a Variant of Uncertain Significance by a single clinical laboratory.

With only one moderate pathogenic criterion (PM2) and no supporting benign criteria, this variant is classified as a Variant of Uncertain Significance per ACMG/AMP 2015 guidelines.

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.376C>A, p.Arg126Ser) that does not fall into the ClinGen SVI PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No pathogenic missense variant at the same amino acid position (Arg126) has been identified to support PS1.	pm5_candidates
PS2	Not met	No de novo observation with confirmed paternity and maternity has been reported for this variant.
PS3	Not met	No well-established in vitro or in vivo functional studies have been identified that demonstrate a damaging effect of this variant on POLD1 protein function.	oncokb
PS4	Not met	No case-control or cohort studies demonstrate significantly increased prevalence of this variant in affected individuals versus controls.	clinvar PMID:25394175
PS5	N/A	PS5 is not part of the generic ACMG/AMP 2015 classification framework being applied.	generic_acmg_combination_rules
PM1	Not met	The variant does not lie within a well-established mutational hotspot or critical functional domain. Residue Arg126 is not in a statistically significant hotspot region.
PM2	Met	This variant is absent from large population databases, consistent with extremely low frequency in the general population and supporting potential pathogenicity.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense variant at the same amino acid residue (Arg126) has been identified in ClinVar or other databases to serve as a comparator for PM5.	pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant.
PP1	Not met	No cosegregation data are available to evaluate segregation of this variant with disease in affected families.
PP2	Not met	No gene-specific missense constraint metric is available to support that POLD1 has a low rate of benign missense variation and that missense variants are a common disease mechanism.
PP3	Not met	Multiple in silico tools do not support a deleterious effect of this variant. REVEL score is 0.461 (indeterminate), BayesDel score is 0.100 (benign-leaning), and SpliceAI delta is 0.00 (no predicted splice impact).	revel bayesdel spliceai
PP4	Not met	No detailed patient phenotype or family history data are available to assess specificity for POLD1-associated disease.
PP5	Not met	The variant is classified as Uncertain Significance in ClinVar by a single clinical laboratory (Ambry Genetics), not as pathogenic. No reputable source reports this variant as pathogenic.	clinvar PMID:25394175
BA1	Not met	The variant is absent from gnomAD population databases; allele frequency does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD population databases; allele frequency does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observation of this variant in a healthy adult individual for a disorder with full penetrance has been reported.
BS3	Not met	No well-established in vitro or in vivo functional studies have been identified that demonstrate no damaging effect of this variant.	oncokb
BS4	Not met	No segregation data in affected families are available to evaluate lack of cosegregation with disease.
BP1	Not met	Although POLD1 loss of function is a supported disease mechanism, there is no evidence that this specific missense variant has been observed in trans with a pathogenic truncating variant in POLD1.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a pathogenic variant in POLD1, which is associated with autosomal dominant cancer predisposition.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions; this is a missense substitution variant.
BP4	Not met	Multiple lines of computational evidence do not convincingly suggest no impact on the gene product. REVEL score (0.461) is indeterminate, and BayesDel (0.100) and SpliceAI (0.00) alone are insufficient to meet BP4 threshold.	revel bayesdel spliceai
BP5	Not met	This variant has not been observed in a case with an alternative molecular basis for disease.
BP6	Not met	No reputable source reports this variant as benign. ClinVar classification is Uncertain Significance, not benign or likely benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact; this is a missense variant (p.Arg126Ser).

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.