Classification rationale

BP4 VUS

POLD1 c.353C>T missense · exon 4

BP4 supporting: REVEL 0.099 is below the benign computational threshold. VUS: BP4 alone is insufficient for the generic ACMG/AMP Likely Benign or Benign thresholds.

BP4 → VUS

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_002691.4 · variants mapped to exon structure

POLD1 NM_002691.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 23 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

Met at supporting: REVEL 0.099 is below the BP4 supporting threshold of <=0.29 for missense variants.

The variant is missense, NP_002682.2:p.(Ser118Phe), so REVEL is the applicable computational path and SpliceAI is excluded.REVEL score is 0.099, meeting BP4 supporting <=0.29 but not the moderate <=0.183 or strong <=0.016 thresholds under the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).BayesDel has no generic ACMG-strength calibration and was not used for BP4.

Assessed · not applied · 8 not met · 15 not assessed

Pathogenic

PS1 Not assessed: no validated pathogenic POLD1 substitution producing the same p.Ser118Phe amino-acid change was identified.

PS2 Not assessed: no documented affected proband with confirmed absence of the variant in both tested biological parents.

PS3 Not assessed: no variant-specific validated functional assay, assay controls, or quantitative biological readout was reported for POLD1 p.Ser118Phe.

PS4 Not assessed: no variant-specific case-control enrichment, odds ratio, likelihood ratio, or affected-versus-control prevalence data are available.

PM1 Not met: POLD1 S118 is not in a documented hotspot, and no approved critical-domain evidence places residue 118 in a PM1 region.

PM2 Not met: aggregate AF is below 0.0001, but ancestry-specific frequencies reach 0.000696185 in gnomAD v2.1 and exceed the PM2 threshold.

PM3 Not assessed: no affected-proband biallelic observation or verified pathogenic variant in trans is documented for this POLD1 variant.

PM5 Not assessed: no validated pathogenic missense comparator at POLD1 residue Ser118 was available for PM5.

PM6 Not assessed: no suspected de novo observation with compatible phenotype and parental testing or parentage information is reported.

PP1 Not assessed: no informative affected-relative or unaffected-relative genotypes and no segregation meioses are documented.

PP2 Not assessed: no gene-specific POLD1 evidence establishes both a dominant missense mechanism and a low benign-missense rate for PP2.

PP3 Not met: REVEL 0.099 is below the PP3 supporting threshold of >=0.644 for missense variants.

PP4 Not assessed: no carrier phenotype or clinical diagnosis is provided to evaluate specificity for a POLD1-related disorder.

PP5 Not met: ClinVar has zero expert-panel submissions for the exact variant and no qualifying Pathogenic or Likely pathogenic expert-panel classification.

Benign

BA1 Not met: the highest default all-comers subpopulation frequency is 0.000696185, far below the 0.05 BA1 threshold.

BS1 Not met: the highest default all-comers subpopulation frequency, 0.000696185, is about 14-fold below the 0.01 BS1 threshold.

BS2 Not met: all available datasets show zero homozygotes, and gnomAD provides no phenotype or age data proving any carrier is a healthy adult.

BS3 Not assessed: no variant-specific validated assay demonstrated preserved POLD1 function with appropriate controls or a quantitative benign-effect result.

BS4 Not assessed: no tested unaffected relatives with documented non-segregation and reliable phenotype information are reported.

BP1 Not assessed: POLD1 is missense here, but predominant truncating-variant disease mechanism has not been established for BP1.

BP2 Not assessed: no documented co-occurrence or phase result shows this variant with another pathogenic or likely pathogenic variant.

BP5 Not assessed: no alternative molecular diagnosis or evidence that another variant explains the patient's phenotype is documented.

BP6 Not met: ClinVar has zero expert-panel submissions, so its ordinary Likely benign laboratory assertions cannot trigger BP6.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 7.87149e-05; MAF= 0.00787%, 127/1613418 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000433406; MAF= 0.04334%, 26/59990 alleles, homozygotes = 0); grpmax FAF= 0.0003034.

v2.1

This variant is present in gnomAD v2.1 (AF= 8.55377e-05; MAF= 0.00855%, 24/280578 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000696185; MAF= 0.06962%, 5/7182 alleles, homozygotes = 0); grpmax FAF= 0.00011513.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0079% · 127 / 1,613,418
0 hom · FAF 0.03%

Admixed American 26 / 59,990	0.043%
Remaining individuals 8 / 62,470	0.013%
European (Finnish) 8 / 63,630	0.013%
European (non-Finnish) 85 / 1,179,886	0.0072%

+ 6 not observed (Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0086% · 24 / 280,578
0 hom · FAF 0.012%

Remaining individuals 5 / 7,182	0.07%
Admixed American 8 / 35,386	0.023%
European (Finnish) 3 / 24,726	0.012%
European (non-Finnish) 8 / 127,774	0.0063%

+ 4 not observed (African/African American, Ashkenazi Jewish, East Asian, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Likely benign (3 clinical laboratories). (ClinVarID = 239345)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.099. BayesDel score = -0.42693.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. POLD1, a DNA polymerase, is infrequently altered by mutation in cancer.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV70957592, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 3 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

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