NM_002691.4:c.2953C>T

POLD1 · NP_002682.2:p.(Arg985Trp) · NM_002691.4

GRCh37: chr19:50919785 C>T · GRCh38: chr19:50416528 C>T

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

PM2 moderate

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Arg985Trp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The POLD1 c.2953C>T (p.Arg985Trp) variant has been reported in ClinVar as a variant of uncertain significance by five clinical laboratories.

This variant is present at very low frequency in population databases, with gnomAD v2.1 AF 1.07182e-05 (2/186598) and gnomAD v4.1 AF 5.15439e-06 (8/1552074), both below the 0.1% PM2 threshold.

Computational evidence is conflicting: SpliceAI predicts possible splice impact with a max delta score of 0.59, whereas REVEL is low at 0.126 and BayesDel is -0.414351, so PP3 and BP4 are not applied.

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 variant is a missense substitution, p.(Arg985Trp), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice-site variants. Although gene-level review supports that loss of function can be a disease mechanism in POLD1, the variant-specific PVS1 scaffold does not support applying PVS1 to this change.	pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No reviewed evidence identified another nucleotide change causing the same amino acid substitution with an established pathogenic classification, so PS1 cannot be assessed from the available evidence.
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 is not assessed.
PS3	Not assessed	No well-established functional study showing a damaging effect of p.(Arg985Trp) was identified, so PS3 is not assessed.	oncokb
PS4	Not assessed	No case-control enrichment or affected-individual series demonstrating a significant excess of this variant in disease was identified, so PS4 is not assessed.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	This residue was not identified in Cancer Hotspots, and available reviewed evidence does not show that p.Arg985 lies in a statistically significant hotspot for this gene. PM1 is therefore not met.	hotspots
PM2	Met	This variant is present at very low frequency in population databases and remains below the non-VCEP PM2 threshold of 0.1% in both datasets reviewed: gnomAD v2.1 AF 1.07182e-05 (0.00107%, 2/186598) and gnomAD v4.1 AF 5.15439e-06 (0.00052%, 8/1552074). This supports PM2.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is used for recessive disorders with evidence of trans occurrence, and no such recessive context or phase data were identified for this variant.
PM4	N/A	This variant is a missense substitution and is not an in-frame deletion, in-frame insertion, or stop-loss variant, so PM4 is not applicable.
PM5	Not assessed	No reviewed evidence identified a different pathogenic missense change at the same amino acid residue, so PM5 is not assessed.
PM6	Not assessed	No apparent de novo report without full parental confirmation was identified for this variant, so PM6 is not assessed.
PP1	Not assessed	No segregation data were identified for this variant, so PP1 is not assessed.
PP2	Not assessed	Available reviewed sources do not establish a gene-level missense pattern that would support PP2 for this variant, so PP2 is not assessed.
PP3	Not met	Computational evidence is conflicting rather than consistently damaging. SpliceAI predicts possible splice impact with a max delta score of 0.59, but missense predictors are low or not damaging (REVEL 0.126 and BayesDel -0.414351). Because the in silico results do not consistently support a deleterious effect, PP3 is not met.	spliceai revel bayesdel
PP4	Not assessed	No individual-level phenotype or family history data were provided that would support a highly specific clinical presentation for this variant, so PP4 is not assessed.
PP5	Not met	ClinVar lists this variant as Uncertain significance with single-submitter review status rather than as a pathogenic or likely pathogenic expert classification, so PP5 is not met.	clinvar
BA1	Not met	Population frequency does not meet the benign stand-alone threshold of 1%. The highest frequency reviewed was 0.00586% in gnomAD v2.1 African/African American and 0.00355% in gnomAD v4.1 South Asian, both far below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not exceed the non-VCEP BS1 threshold of 0.3%. The overall AF is 0.00107% in gnomAD v2.1 and 0.00052% in gnomAD v4.1, both well below 0.3%, so BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	Available reviewed evidence does not document this variant in a sufficient number of unaffected adults for the relevant disorder context, so BS2 is not assessed.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing a normal or non-damaging effect of p.(Arg985Trp) was identified, so BS3 is not assessed.	oncokb
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 is not assessed.
BP1	Not assessed	Available reviewed evidence does not establish that missense variants in this gene are generally a poor mechanism of disease, so BP1 is not assessed.
BP2	Not assessed	No phase or co-occurrence data with another pathogenic variant were identified for this variant, so BP2 is not assessed.
BP3	N/A	This variant is not an in-frame deletion or insertion in a repetitive region, so BP3 is not applicable.
BP4	Not met	Computational evidence does not consistently support a benign interpretation. Although REVEL is low at 0.126 and BayesDel is -0.414351, SpliceAI predicts possible splice impact with a max delta score of 0.59. Because the in silico evidence is conflicting, BP4 is not met.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular explanation or independent cause for the phenotype was identified from the available evidence, so BP5 is not assessed.
BP6	Not met	ClinVar does not provide a benign or likely benign reputable-source classification for this variant; the reported classification is Uncertain significance, so BP6 is not met.	clinvar
BP7	N/A	This variant is a missense substitution rather than a synonymous or deep intronic change, so BP7 is not applicable.

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