LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-21
Case ID: NM_001308632.1_c.845C_T_20260721_045639
Framework: ACMG/AMP 2015
Variant classification summary

NM_001308632.1:c.845C>T

POLD1  · NP_001295561.1:p.(Thr282Met)  · NM_001308632.1
GRCh37: chr19:50905873 C>T  ·  GRCh38: chr19:50402616 C>T
Gene: POLD1 Transcript: NM_001308632.1
Final call
VUS
PM2 supporting BP4 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
POLD1
Transcript
NM_001308632.1
Protein
NP_001295561.1:p.(Thr282Met)
gnomAD AF
1.0176809341293295e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_001308632.1:c.845C>T (p.Thr282Met) is a missense variant in exon 7 of POLD1. This variant is extremely rare in population databases, with an allele frequency of approximately 0.001% in gnomAD (2/185,056 alleles in v2.1; 16/1,572,202 alleles in v4.1), meeting PM2 at supporting strength.
2
Multiple in silico tools predict a benign effect: REVEL score 0.163, BayesDel score -0.403, and SpliceAI max delta score 0.07, meeting BP4 at supporting strength.
3
This variant is reported in ClinVar (VCV000537064) as Uncertain significance by two clinical laboratories and Likely benign by one laboratory, with review status 'criteria provided, single submitter.' No expert panel classification is available.
4
The variant has been observed in COSMIC (COSV70954170) in 4 somatic cancer samples, but no germline functional data or case-control studies were identified.
5
Two publications in the case record were reviewed for variant-specific evidence. PMID:35534704 (de Oliveira et al., 2022) reported POLD1 as a gene harboring pathogenic/likely pathogenic variants in a Brazilian hereditary cancer cohort but did not mention c.845C>T specifically. PMID:25394175 (Hampel et al., 2015) is an ACMG/NSGC practice guideline for cancer predisposition referral and contains no variant-specific data.
6
Overall, the evidence yields one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4). The variant remains of uncertain significance.
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.Thr282Met) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 under the ClinGen SVI PVS1 framework (PMC6185798).
pvs1_generic_framework
PS1 Not met No evidence of a different nucleotide change at the same codon producing the same missense change (Thr282Met) was identified in any data source.
PS2 Not met No de novo observation was reported for this variant in any data source. The available publications and ClinVar submissions do not include de novo testing or parent-of-origin data.
PS3 Not met No variant-specific functional data was identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no reviewed functional evidence. No publication in this case reported experimental functional characterization of p.Thr282Met or a systematically characterized range that includes position 282.
oncokb
PS4 Not met No case-control data or statistically significant enrichment of this variant in affected individuals was identified. The variant has been observed in ClinVar (3 submissions: 2 VUS, 1 LB) and in COSMIC (4 somatic occurrences), but neither source provides odds-ratio or case-control evidence required for PS4.
clinvar
PS5 Not met No different nucleotide change at the same codon producing the same missense change was identified as pathogenic in any data source. No basis for PS5 application exists.
PM1 Not met The variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org. While POLD1 position 282 is within the exonuclease domain region, no variant-specific domain-level literature characterizing this residue as a critical functional site was identified in the case materials.
PM2 Met This variant is extremely rare in population databases. gnomAD v2.1 reports 2 alleles in 185,056 (AF=0.00108%) and gnomAD v4.1 reports 16 alleles in 1,572,202 (AF=0.00102%), both well below the 0.1% threshold for PM2. No homozygotes have been observed.
gnomad_v2 gnomad_v4
PM5 Not met No same-residue comparator missense variants with established pathogenicity were identified. The automated PM5 candidate search found no eligible ClinVar entries at position 282.
pm5_candidates
PM6 Not met No de novo observation was reported for this variant. PM6 requires a confirmed de novo event with maternity and paternity confirmed; no such data exists in this case.
PP1 Not met No cosegregation data is available for this variant. No family studies or pedigree analysis were identified in the case materials.
PP2 Not met While POLD1 is a cancer predisposition gene with known pathogenic missense variants, no gene-level missense constraint data (such as missense Z-score or gnomAD constraint metrics) was available in this case to establish a low rate of benign missense variation required for PP2.
PP3 Not met Multiple in silico tools support a benign impact. REVEL score is 0.163 (below the typical pathogenic threshold of 0.5). BayesDel score is -0.403 (negative, indicative of benign). SpliceAI max delta is 0.07 (no predicted splicing impact). Computational evidence does not support a deleterious effect.
revel bayesdel spliceai
PP4 Not met No specific patient phenotype data is available for this variant. The ClinVar submissions do not include detailed clinical phenotypes, and no publications report variant-specific clinical features.
PP5 Not met ClinVar reports this variant as Uncertain significance (2 clinical laboratories) and Likely benign (1 clinical laboratory) with review status 'criteria provided, single submitter.' No expert panel review exists. The current classification does not support a reputable source asserting pathogenicity required for PP5. Even under the PP5 global rule (ClinVar 3-star expert panel for supporting), there is no expert panel submission.
clinvar
BA1 Not met The overall gnomAD allele frequency is approximately 0.001%, far below the 1% threshold required for BA1.
gnomad_v2 gnomad_v4
BS1 Not met The overall gnomAD allele frequency is approximately 0.001%, well below the 0.3% threshold required for BS1.
gnomad_v2 gnomad_v4
BS2 Not met No homozygous observations exist in gnomAD (0 homozygotes across all datasets). BS2 requires observation in homozygous state in healthy adults for a fully penetrant dominant disorder. This variant is too rare to satisfy BS2.
gnomad_v2 gnomad_v4
BS3 Not met No experimental functional studies were identified that demonstrate no deleterious effect of this variant. The available in silico predictions lean benign (REVEL 0.163, BayesDel -0.403), but these are computational, not experimental, evidence and belong under BP4, not BS3.
BS4 Not met No segregation data exists for this variant. BS4 requires lack of cosegregation in affected family members, and no family studies were identified in this case.
BP1 Not met BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. POLD1 is associated with polymerase proofreading-associated polyposis (PPAP), and pathogenic missense variants in the exonuclease domain are a well-established disease mechanism alongside truncating variants. Therefore, POLD1 is not a gene where disease is caused primarily by truncating variants alone.
pvs1_gene_context
BP2 Not met No observation in trans with a known pathogenic variant was reported. This variant is too rare in population databases to assess phase with other variants.
BP4 Met Multiple lines of computational evidence support a benign impact. REVEL score is 0.163 (below the typical 0.5 threshold for pathogenicity). BayesDel score is -0.403 (negative, consistent with benign). SpliceAI max delta is 0.07 (no predicted splicing impact). Together these in silico predictions suggest the variant does not disrupt protein function or splicing.
revel bayesdel spliceai
BP5 Not met No observation of this variant in a case with an alternative molecular basis for disease was identified. No cases were reported where a different pathogenic variant explains the phenotype in an individual also carrying c.845C>T.
BP6 Not met ClinVar reports this variant as Uncertain significance (2 clinical laboratories) and Likely benign (1 clinical laboratory) with review status 'criteria provided, single submitter.' The Likely benign classification from Ambry Genetics is a single submitter without expert panel review. Even under the BP6 global rule (ClinVar 3-star expert panel for supporting benign), there is no expert panel submission for this variant.
clinvar
BP7 N/A BP7 applies specifically to synonymous (silent) variants. This variant is a missense substitution (c.845C>T, p.Thr282Met) and does not qualify for BP7.
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