Variant classification summary

NM_002691.4:c.3218+4T>C

POLD1 · NP_002682.2:p.? · NM_002691.4

GRCh37: chr19:50920530 T>C · GRCh38: chr19:50417273 T>C

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.?

gnomAD AF

6.312549474606508e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 total allele frequency is 6.31e-06 (10/1,584,146 alleles, zero homozygotes) and the variant is absent from gnomAD v2.1.

2

BP4 supporting: SpliceAI maximum delta 0.025 is below the 0.1 threshold, so no splice-altering effect is predicted for this intronic donor +4 change.

3

VUS: one supporting pathogenic criterion plus one supporting benign criterion satisfies no ACMG/AMP 2015 combination rule.

Final determination: Under the generic ACMG/AMP 2015 rules, one supporting pathogenic criterion (PM2) together with one supporting benign criterion (BP4) satisfies no Pathogenic, Likely Pathogenic, Benign or Likely Benign combination, 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	Not met	Not met: c.3218+4T>C lies outside the canonical +/-1,2 donor site and SpliceAI max delta 0.025 predicts no aberrant splicing.	spliceai pvs1_variant_assessment pvs1_generic_framework pvs1_gene_context clinvar
PS1	N/A	Not applicable: c.3218+4T>C is intronic with protein consequence p.?, producing no amino-acid change for a same-change comparison.	final_classification_framework clinvar pm5_candidates PMID:25394175
PS2	Not assessed	Not assessed: no proband, parental testing, or pedigree data exists, so a confirmed de novo occurrence cannot be evaluated.	clinvar
PS3	Not met	Not met: no functional assay of c.3218+4T>C exists - neither ClinVar submitter nor any retrieved full text reports a splice or protein-function study.	clinvar final_classification_framework PMID:17576681 PMID:9536098 PMID:25394175
PS4	Not met	Not met: no case-control or cohort enrichment data exists for this variant, and no numeric PS4 threshold is available to compare against.	clinvar gnomad_v4 PMID:25394175
PM1	N/A	Not applicable: c.3218+4T>C is intronic with protein consequence p.? and no occupied domain, and POLD1 has no VCEP domain table.	final_classification_framework pvs1_variant_assessment pm5_candidates clinvar
PM2	Met	Met (supporting): gnomAD v4.1 all-comers AF 6.31e-06 (10/1,584,146 alleles, 0 homozygotes) and absent from v2.1, about 16-fold below the 0.0001 PM2 threshold.	gnomad_v4 gnomad_v2 clinvar generic_acmg_combination_rules
PM3	N/A	Not applicable: POLD1 cancer predisposition is autosomal dominant (heterozygous loss-of-function), so the recessive in-trans PM3 criterion does not apply.	clinvar oncokb final_classification_framework
PM4	Not met	Not met: this intronic substitution is not an in-frame indel or stop-loss, and SpliceAI 0.025 predicts no length-altering exon skipping.	spliceai pvs1_variant_assessment clinvar
PM5	N/A	Not applicable: c.3218+4T>C is intronic with protein consequence p.?, so no residue exists and no same-residue comparator can be defined.	pm5_candidates final_classification_framework clinvar PMID:25394175
PM6	Not assessed	Not assessed: with no proband or parental data, neither confirmed nor assumed de novo status can be established for this variant.	clinvar
PP1	Not assessed	Not assessed: no pedigree, affected relatives, or genotype data, so PP1 co-segregation and meioses cannot be counted.	clinvar
PP2	N/A	Not applicable: c.3218+4T>C is intronic with protein consequence p.?, not a missense variant, so this missense-specific gene criterion cannot apply.	final_classification_framework pvs1_gene_context pm5_candidates
PP3	Not met	Not met: SpliceAI max delta 0.025 falls below the 0.2 supporting threshold for PP3.	spliceai
PP4	Not assessed	Not assessed: no proband phenotype or family history is recorded anywhere in this case, so phenotype specificity for POLD1 disease cannot be judged.	clinvar pvs1_gene_context
PP5	Not met	Not met: the only ClinVar submissions for this exact variant are two clinical-laboratory Uncertain significance calls with zero expert-panel submissions.	clinvar final_classification_framework
BA1	Not met	Not met: gnomAD v4.1 all-comers AF 6.31e-06 (10/1,584,146 alleles), roughly four orders of magnitude below the 0.05 BA1 threshold.	gnomad_v4 gnomad_v2 generic_acmg_combination_rules
BS1	Not met	Not met: gnomAD v4.1 AF 6.31e-06 versus the 0.01 BS1 threshold, roughly 1,500-fold below even using the highest-ancestry estimate.	gnomad_v4 gnomad_v2 generic_acmg_combination_rules
BS2	Not met	Not met: zero homozygotes in gnomAD v4.1 (10/1,584,146 alleles) and POLD1 disease is adult-onset, incompletely penetrant cancer predisposition, so BS2's premise fails.	gnomad_v4 clinvar generic_acmg_combination_rules
BS3	Not met	Not met: no functional study of c.3218+4T>C reports normal splicing or protein function; SpliceAI 0.025 is computational, not assay, evidence.	clinvar final_classification_framework PMID:17576681 PMID:9536098 PMID:25394175
BS4	Not assessed	Not assessed: no family genotype data exists, so non-segregation cannot be demonstrated in this variant's relatives.	clinvar
BP1	N/A	Not applicable: c.3218+4T>C is intronic with protein consequence p.?, not a missense variant, so the missense-specific BP1 cannot apply.	final_classification_framework pvs1_gene_context
BP2	Not met	Not met: no phase data exist, so c.3218+4T>C was never observed in cis or in trans with a pathogenic POLD1 variant.	clinvar final_classification_framework
BP3	N/A	Not applicable: BP3 covers in-frame indels in repeat regions, while this is a single-nucleotide intronic donor-site substitution.	pvs1_variant_assessment spliceai
BP4	Met	Met at supporting: SpliceAI max delta 0.025 is at or below the 0.1 splice-impact BP4 threshold.	spliceai
BP5	Not assessed	Not assessed: the case has no proband molecular or clinical data, so no alternate molecular basis for disease can be evaluated for BP5.	clinvar
BP6	Not met	Not met: no expert-panel Benign/Likely benign classification exists for this exact variant, whose ClinVar entries are both Uncertain significance.	clinvar final_classification_framework
BP7	N/A	Not applicable: c.3218+4T>C is an intronic donor-site change, not a synonymous variant.

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