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POLD1c.376C>AUncertain significance
Print report
Variant interpretation report

POLD1 c.376C>A, p.(Arg126Ser)

NM_002691.4:c.376C>A NP_002682.2:p.(Arg126Ser) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About POLD1

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

This variant is absent from large population databases, consistent with extremely low frequency in the general population and supporting potential pathogenicity.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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 moderate; combination = 1 moderate, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

27 criteria with recorded statuses: 1 met · 21 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 1

PM2 ModerateThis variant is absent from large population databases, consistent with extremely low frequency in the general population and supporting potential pathogenicity. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes/genomes).
  • Absent from gnomAD-Canada v1.0 (genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 21 · evaluated, threshold not reached

PS1 No pathogenic missense variant at the same amino acid position (Arg126) has been identified to support PS1. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search found zero same-residue comparator variants
  • no ClinVar pathogenic/likely pathogenic entries at Arg126.
Still missing
  • No curated database of residue-level pathogenic variants available for POLD1.
Sources
pm5_candidates
PS2 No de novo observation with confirmed paternity and maternity has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data identified in ClinVar
  • literature
  • or any other source.
Still missing
  • No parental testing data available.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence.
Still missing
  • No functional assays performed on p.Arg126Ser.
  • No literature reporting functional characterization of this specific variant.
Sources
oncokb ↗
PS4 No case-control or cohort studies demonstrate significantly increased prevalence of this variant in affected individuals versus controls. Details ▾Hide ▴
Evidence considered
  • ClinVar reports a single submission (Ambry Genetics) with no associated case data. PMID:25394175 is a general cancer referral guideline and does not report any cases carrying this variant.
Still missing
  • No case counts or cohort prevalence data available.
Sources
clinvar ↗PMID:25394175 ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots analysis did not identify this residue as significant
  • exact variant not listed in hotspot database.
Still missing
  • No POLD1-specific domain-level constraint or functional domain map available for this assessment.
PM6 No de novo observation has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data identified in any source.
Still missing
  • No parental testing data available.
PP1 No cosegregation data are available to evaluate segregation of this variant with disease in affected families. Details ▾Hide ▴
Evidence considered
  • No family studies or segregation analyses identified for this variant.
Still missing
  • No family-based segregation data available.
PP2 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. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for POLD1. No missense Z-score or missense constraint data accessible.
Still missing
  • No gene-level missense constraint metric available for POLD1.
PP3 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). Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.461 (indeterminate
  • below the typical pathogenic threshold of >0.7).
  • BayesDel score: 0.10049 (low
  • not supporting pathogenicity).
  • SpliceAI max delta: 0.00 (no predicted splice alteration).
Sources
revelbayesdelspliceai ↗
PP4 No detailed patient phenotype or family history data are available to assess specificity for POLD1-associated disease. Details ▾Hide ▴
Evidence considered
  • ClinVar submission by Ambry Genetics does not include detailed phenotype information. No case-level phenotype data identified in the literature.
Still missing
  • No patient phenotype information available for review.
PP5 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. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Uncertain significance
  • criteria provided
  • single submitter (Ambry Genetics).
  • PMID:25394175 is a general ACMG/NSGC practice guideline for cancer predisposition referral
  • it does not discuss this specific variant.
Sources
clinvar ↗PMID:25394175 ↗
BA1 The variant is absent from gnomAD population databases; allele frequency does not exceed the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • Absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from gnomAD population databases; allele frequency does not exceed the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • Absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No observation of this variant in a healthy adult individual for a disorder with full penetrance has been reported. Details ▾Hide ▴
Evidence considered
  • No data on variant observation in healthy adult controls beyond population database absence.
Still missing
  • No phenotype-genotype data for healthy carriers.
BS3 No well-established in vitro or in vivo functional studies have been identified that demonstrate no damaging effect of this variant. Details ▾Hide ▴
Evidence considered
  • OncoKB reports Unknown Oncogenic Effect
  • no variant-specific functional evidence available.
Still missing
  • No functional assays performed on p.Arg126Ser.
Sources
oncokb ↗
BS4 No segregation data in affected families are available to evaluate lack of cosegregation with disease. Details ▾Hide ▴
Evidence considered
  • No family-based segregation studies identified.
Still missing
  • No segregation data available.
BP1 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. Details ▾Hide ▴
Evidence considered
  • POLD1 LoF mechanism supported by literature
  • however
  • BP1 requires observation of the missense variant in trans with a pathogenic truncating variant
  • which is not available.
Still missing
  • No trans-configuration data with a pathogenic truncating POLD1 variant.
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a pathogenic variant in POLD1, which is associated with autosomal dominant cancer predisposition. Details ▾Hide ▴
Evidence considered
  • No trans data available.
Still missing
  • No phase or trans-configuration data.
BP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.461 (indeterminate
  • does not clearly predict benign effect).
  • BayesDel: 0.10049 (low score but requires corroboration).
  • SpliceAI: 0.00 (no splicing impact).
Still missing
  • REVEL score is in the indeterminate zone
  • stronger and more consistent benign predictions would be needed to meet BP4.
Sources
revelbayesdelspliceai ↗
BP5 This variant has not been observed in a case with an alternative molecular basis for disease. Details ▾Hide ▴
Evidence considered
  • No data on alternative molecular diagnoses in carriers of this variant.
BP6 No reputable source reports this variant as benign. ClinVar classification is Uncertain Significance, not benign or likely benign. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Uncertain significance by a single submitter (Ambry Genetics).
Sources
clinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis 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. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution in exon 4
  • PVS1 is not applicable to missense variants under the ClinGen PVS1 decision tree (PMC6185798).
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned zero same-residue comparator variants
  • unable to confirm classic same-residue PM5 semantics.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions; this is a missense substitution variant. Details ▾Hide ▴
Evidence considered
  • Variant type is a single-nucleotide substitution (c.376C>A)
  • not an in-frame indel.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; this is a missense variant (p.Arg126Ser). Details ▾Hide ▴
Evidence considered
  • Variant type is missense
  • not synonymous.
PS5 N/APS5 is not part of the generic ACMG/AMP 2015 classification framework being applied. Details ▾Hide ▴
Evidence considered
  • Generic ACMG/AMP 2015 framework (PMID:25741868) does not include PS5
  • this criterion was introduced in later ClinGen adaptations.
Sources
generic_acmg_combination_rules

Identifiers

Gene
POLD1
Transcript
NM_002691.4
Coding (HGVS c.)
NM_002691.4:c.376C>A
Protein (HGVS p.)
NP_002682.2:p.(Arg126Ser)
GRCh38
chr19:50401837 C>A
GRCh37
chr19:50905094 C>A
ClinVar
4668398

Gene diagram

Every interpreted variant in POLD1, mapped onto the exon structure of NM_002691.4. Select a row to find it on the plot.

POLD1NM_002691.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
0.461
BayesDel
0.100

How the predictions were used

PP3 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). Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.461 (indeterminate
  • below the typical pathogenic threshold of >0.7).
  • BayesDel score: 0.10049 (low
  • not supporting pathogenicity).
  • SpliceAI max delta: 0.00 (no predicted splice alteration).
Sources
revelbayesdelspliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.461 (indeterminate
  • does not clearly predict benign effect).
  • BayesDel: 0.10049 (low score but requires corroboration).
  • SpliceAI: 0.00 (no splicing impact).
Still missing
  • REVEL score is in the indeterminate zone
  • stronger and more consistent benign predictions would be needed to meet BP4.
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; this is a missense variant (p.Arg126Ser). Details ▾Hide ▴
Evidence considered
  • Variant type is missense
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.461. BayesDel score = 0.10049.

1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • 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.
    Hampel H et al. · 2015
    ACMG/NSGC joint practice guideline providing referral indications for cancer predisposition assessment. This is a general framework document that does not discuss the POLD1 gene or NM_002691.4:c.376C>A.
    Does not name this variant
    PMID 25394175 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 1 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4668398)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.461. BayesDel score = 0.10049.

Functional

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.