POLD1 encodes the catalytic subunit of DNA polymerase delta, an enzyme that carries both DNA synthesis and proofreading (3' to 5' exonuclease) activities and is essential for accurate DNA replication and repair. Germline mutations in its exonuclease domain cause polyposis and predispose people to colorectal, endometrial, and possibly brain cancers. In cancer, POLD1 defects impair replication fidelity, leading to the accumulation of many mutations (an ultra-mutated phenotype) that may make tumors more responsive to immunotherapy, though somatic POLD1 mutations are rare.
This variant
POLD1 encodes the catalytic subunit of DNA polymerase delta, whose proofreading exonuclease domain is the site of germline missense variants that cause polyposis and colorectal/endometrial cancer predisposition. This missense variant, p.Arg521Gln, lies in that domain yet outside its core catalytic motifs, and it is rare but not absent in the population, with no functional, de novo, or segregation evidence available. The VUS classification therefore means current evidence is insufficient to determine whether this variant affects proofreading and cancer risk.
Transcript
NM_002691.4
HGVS · transcript:coding
NM_002691.4:c.1562G>A
GRCh38
chr19:50407050 G>A
GRCh37
chr19:50910307 G>A
BasisVUS: with only PM2 met (supporting strength), no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination is satisfied under the generic ACMG/AMP 2015 rules.▾
VUS: with only PM2 met (supporting strength), no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination is satisfied under the generic ACMG/AMP 2015 rules.
Classification rationale
PM2VUS
POLD1 c.1562G>Amissense · exon 13
PM2 (Supporting): gnomAD v4.1 allele frequency 0.016% (AF 0.000161) is below the 0.1% rare-variant threshold. Overall classification: VUS - a single supporting-strength criterion satisfies no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination under the generic ACMG/AMP 2015 rules.
PM2→VUS
Gene diagram
· NM_002691.4 · variants mapped to exon structure
POLD1NM_002691.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in POLD1—click a row to locate it on the plot · use the link column to open its page
Variant ↕
Protein
Location
Classification
Link
Applied criteria · 1 applied · 22 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
✓
PM2supportingPathogenic
Met (supporting): gnomAD v4.1 allele frequency 0.016% (AF 0.000161) is below the 0.1% rare-variant threshold.
No POLD1-specific ClinGen VCEP specification or local gene framework was available; generic ACMG/AMP fallback applies.gnomAD v4.1: 260/1,613,618 alleles, AF 0.016113%, zero homozygotes, and grpmax FAF 0.017902%. gnomAD v2.1: 33/282,008 alleles, AF 0.011702%, zero homozygotes, grpmax FAF 0.016803%. gnomAD-Canada: 2/18,344 alleles, AF 0.010903%, zero homozygotes.Generic fallback operational population threshold: PM2 supporting is applicable when population AF is below 0.1%.
Assessed · not applied
· 10 not met · 12 not assessed
Pathogenic
PS1Not met: no alternate nucleotide change producing p.Arg521Gln has been established as pathogenic; ClinVar shows only uncertain/conflicting submissions.
PS2Not assessed: no parental genotypes or confirmed de novo occurrence was documented.
PS3Not assessed: no validated functional assay directly testing p.Arg521Gln enzyme function was available.
PS4Not assessed: no case-control enrichment or case-excess analysis for this exact variant was identified.
PM1Not met: p.Arg521Gln lies outside the core Exo catalytic motifs, in a domain region where benign/uncertain missense variation is documented.
PM5Not assessed: no alternate missense at codon 521 established as pathogenic was identified.
PM6Not assessed: no de novo occurrence with unconfirmed parentage was documented.
PP1Not assessed: no informative cosegregation data were available for this variant.
PP2Not met: benign missense variation is not rare in the exonuclease domain; none of five surveyed outside-active-site missense variants reached pathogenic classification.
PP3Not met: REVEL 0.278 falls in the gray zone (0.250-0.750), reaching neither the PP3 nor BP4 threshold.
PP4Not assessed: early-onset colorectal cancer alone is not a highly specific phenotype, and no POLD1-associated mutational signatures were present.
PP5Not met: ClinVar has no expert-panel pathogenic or likely pathogenic assertion for this variant.
Benign
BA1Not met: highest population frequency (grpmax FAF 0.018%) is far below the 1% BA1 threshold.
BS1Not met: highest subgroup allele frequency 0.040% remains below the 0.3% BS1 threshold.
BS2Not assessed: no observations in unaffected, appropriately aged individuals with phenotype information were available.
BS3Not assessed: no validated functional assay result, benign or damaging, was available for this variant.
BS4Not assessed: no informative lack of segregation was documented for this variant.
BP1Not met: POLD1 cancer predisposition is caused predominantly by missense, not truncating, variants.
BP2Not assessed: no observation of this variant in cis or trans with a pathogenic variant was available.
BP4Not met: REVEL 0.278 is above the <0.25 BP4 threshold.
BP5Not assessed: no independently established alternate molecular diagnosis explaining the phenotype was identified.
BP6Not met: ClinVar has no expert-panel benign or likely benign assertion for this variant.
N/A · 5PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000161129; MAF= 0.01611%, 260/1613618 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000288074; MAF= 0.02881%, 18/62484 alleles, homozygotes = 0); grpmax FAF= 0.00017902.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000117018; MAF= 0.01170%, 33/282008 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000277316; MAF= 0.02773%, 2/7212 alleles, homozygotes = 0); grpmax FAF= 0.00016803.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00010902747492368077, 2/18344 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.016%
· 260 / 1,613,618
0 hom · FAF 0.018%
Remaining individuals
18 / 62,484
0.029%
European (non-Finnish)
236 / 1,180,006
0.02%
African/African American
3 / 74,908
0.004%
Admixed American
2 / 59,966
0.0033%
European (Finnish)
1 / 63,692
0.0016%
+ 5 not observed (Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.012%
· 33 / 282,008
0 hom · FAF 0.017%
Remaining individuals
2 / 7,212
0.028%
European (non-Finnish)
29 / 128,564
0.023%
African/African American
2 / 24,862
0.008%
+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
gnomAD Canada 🇨🇦
0.011%
· 2 / 18,344
0 hom · FAF 0.003%
European (non-Finnish)
2 / 11,692
0.017%
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 239244)
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.
Triaged references · 9 PMIDs not cited in assessment
23263490 ↗Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.CLINVAR
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
26133394 ↗POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance.CLINVAR
26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.CLINVAR
32792570 ↗Role of POLE and POLD1 in familial cancer.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
28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.CLINVAR
