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NM_002691.4:c.1681C>T
p.Arg561Trp · POLD1
ACMG/AMP
0%
complete
Final classification
VUS
PM2
POLD1
c.1681C>T
p.Arg561Trp
missense · exon 13
Gene context NCBI Gene ↗ OncoKB ↗

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 p.Arg561Trp is a missense change in the catalytic subunit of DNA polymerase delta that lies outside the exonuclease (proofreading) domain (residues ~243-477), the region where heterozygous germline missense variants causing polymerase proofreading-associated polyposis and colorectal/endometrial cancer predisposition are established.

Transcript
NM_002691.4
HGVS · transcript:coding
NM_002691.4:c.1681C>T
GRCh38
chr19:50407169 C>T
GRCh37
chr19:50910426 C>T
VUS: PM2 (supporting) is the only applied criterion, and one supporting criterion alone reaches no pathogenic or benign ACMG/AMP combination threshold.
Classification rationale
PM2 VUS
POLD1 c.1681C>T missense · exon 13

PM2 supporting: allele frequency 8.18e-06 in gnomAD v2.1 and 6.24e-07 in gnomAD v4.1 is far below the 0.0001 rarity cutoff, with zero homozygotes.

PM2 → 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
PM2 supporting Pathogenic
Met at supporting strength: total allele frequency 8.18e-06 in gnomAD v2.1 sits below the 0.0001 PM2 threshold, with zero homozygotes and absence from gnomAD-Canada.
gnomAD v2.1 total AF 8.177350374931515e-06 (2/244,578 alleles, exome-only; genome AN = 0), homozygotes = 0; popmax Admixed American AF 2.93807e-05 (1/34,036); NFE AF 9.13e-06 (1/109,528); remaining ancestries 0.gnomAD v4.1 total AF 6.243514549261955e-07 (1/1,601,662 alleles), homozygotes = 0; popmax Admixed American AF 1.68095e-05 (1/59,490); remaining ancestries 0.gnomAD-Canada v1.0 (HostSeq genomes): variant absent.
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 13 not met · 10 not assessed
Pathogenic
PS1 Not met: no pathogenic variant shares this p.Arg561Trp change, and c.1681C>T is the only substitution at codon 561 (CGG) able to encode tryptophan.
PS2 Not assessed: no proband or parental-testing data exists in this case, so a de novo occurrence with confirmed parentage cannot be established.
PS3 Not assessed: no functional assay data for POLD1 p.Arg561W were identified, so the PS3 requirement for a well-established damaging-effect study is unmet.
PS4 Not met: no case-control or case-series data exist for c.1681C>T, so no odds ratio could be computed against the PS4 enrichment requirement.
PM1 Not met: CancerHotspots found no hotspot at R561, which lies outside the POLD1 exonuclease domain (residues ~243-477) where pathogenic missense variants cluster.
PM3 Not assessed: no phase, zygosity or second-allele data exists for this variant, so a trans configuration with a pathogenic POLD1 allele cannot be established.
PM5 Not met: the only same-residue comparators, p.Arg561Gln and p.Arg561Gly, are both classified Uncertain significance in ClinVar, so no pathogenic comparator exists.
PM6 Not assessed: no proband or parental data is present in this case, so an assumed de novo event cannot be asserted for this variant.
PP1 Not assessed: no pedigree or affected-relative genotype data exists in this case, so co-segregation (zero informative meioses) cannot be evaluated.
PP2 Not met: POLD1 is not significantly missense-constrained in gnomAD (missense Z 2.46 v2.1.1 and 2.75 v4.1, both below 3.09), so a low rate of benign missense variation is unproven.
PP3 Not met: REVEL 0.386 is below the 0.644 missense PP3 supporting cutoff.
PP4 Not assessed: no proband phenotype or family history is available, and ClinVar condition labels are gene-level rather than patient-specific.
PP5 Not met: ClinVar VCV000469212 is Uncertain significance from two single-submitter clinical laboratories, with no expert-panel classification.
Benign
BA1 Not met: the highest ancestry-specific allele frequency, 2.94e-05 (gnomAD v2.1 Admixed American), is far below the 0.05 BA1 stand-alone threshold.
BS1 Not met: the maximum observed allele frequency, 2.94e-05 (gnomAD v2.1 Admixed American), is roughly 340-fold below the 0.01 BS1 threshold.
BS2 Not met: zero homozygotes in gnomAD v2.1/v4.1, and POLD1 cancer predisposition is adult-onset with incomplete penetrance, not a fully penetrant early-onset disorder.
BS3 Not assessed: no functional study of POLD1 p.Arg561W was found, so absence of a damaging effect cannot be demonstrated for BS3.
BS4 Not assessed: no family segregation data exists in this case, so non-segregation of this variant with disease cannot be demonstrated.
BP1 Not met: POLD1 pathogenic missense variants are established (ClinVar Pathogenic/Likely pathogenic p.Leu474Pro and p.Ser478Asn), so disease is not caused by truncating variants alone.
BP2 Not assessed: this case records no cis/trans phase or second POLD1 variant, so neither the dominant-trans nor the cis limb of BP2 can be evaluated.
BP4 Not met: REVEL 0.386 is above the 0.29 BP4 supporting cutoff, a gray-zone result.
BP5 Not assessed: no case carrying c.1681C>T is described, so no alternate molecular basis for disease could be documented.
BP6 Not met: no expert-panel Benign or Likely benign classification exists; ClinVar VCV000469212 is Uncertain significance from two clinical laboratories.
N/A · 4 PVS1 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.24351e-07; MAF= 0.00006%, 1/1601662 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.68095e-05; MAF= 0.00168%, 1/59490 alleles, homozygotes = 0).
v2.1
This variant is present in gnomAD v2.1 (AF= 8.17735e-06; MAF= 0.00082%, 2/244578 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.93807e-05; MAF= 0.00294%, 1/34036 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05% · 1 / 1,601,662
0 hom
Admixed American
1 / 59,490
0.0017%
+ 9 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.00082% · 2 / 244,578
0 hom
Admixed American
1 / 34,036
0.0029%
European (non-Finnish)
1 / 109,528
0.00091%
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 469212)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.386. BayesDel score = 0.0477232.
SpliceAI ↗
Functional / OncoKB screenshot
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 screenshot
COSMIC
Cancer hotspots screenshot
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; COSV70957138, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Rule & framework references · cited for criterion definitions, not variant evidence
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.
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots