Variant classification summary

NM_002691.4:c.1275C>T

POLD1 · NP_002682.2:p.(Ala425=) · NM_002691.4

GRCh37: chr19:50909471 C>T · GRCh38: chr19:50406214 C>T

Gene: POLD1 Transcript: NM_002691.4

Final call

Likely Benign

BS1 strong BP4 supporting BP7 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Ala425=)

gnomAD AF

0.0012076202136663697 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1 (Strong): gnomAD v4.1 allele frequency up to 1.9228% (Ashkenazi Jewish) is far too common for a rare POLD1 cancer-predisposition disorder.

2

BP4 (Supporting): SpliceAI max delta 0.035 predicts no splicing consequence, below the ~0.1 threshold.

3

BP7 (Supporting): synonymous change with no predicted splice-site impact.

4

Under the generic ACMG/AMP 2015 combination rules, BS1 (strong) together with BP4 and BP7 (supporting) supports a Likely Benign classification.

Final determination: 1 strong benign + 2 supporting benign criteria, with no conflicting pathogenic evidence, maps to Likely Benign under generic ACMG/AMP 2015.

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	Not applicable: this is a synonymous change, so no null-variant mechanism (nonsense-mediated decay, truncation, or splice disruption) is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: no amino acid is altered (p.(Ala425=)), so there is no change to compare with a previously pathogenic variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no de novo observation with parental genotypes or parentage confirmation was available.
PS3	Not assessed	Not assessed: no functional studies of this variant (e.g., polymerase fidelity or splicing assays) were available.
PS4	Not assessed	Not assessed: no case-control or case-series data involving this exact variant were available.
PM1	N/A	Not applicable: no altered residue exists to evaluate for mutational hot-spot or critical-domain membership.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 allele frequency 0.1208% (up to 1.9228% in Ashkenazi Jewish) shows the variant is too common to be rare.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no affected individual carrying this variant opposite a pathogenic POLD1 variant was documented.
PM4	N/A	Not applicable: no protein length change occurs, so there is nothing for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare with a previously pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo observation with parental testing was available.
PP1	Not assessed	Not assessed: no informative affected relatives or segregation data were reported.
PP2	N/A	Not applicable: no missense change is present, so the gene's missense-constraint properties do not apply.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.035 shows no predicted splice impact, and no missense predictor applies to a synonymous change.	spliceai
PP4	Not assessed	Not assessed: no affected-individual phenotype or phenotypic segregation data were provided.
PP5	Not met	Not met: ClinVar reports no expert-panel submission for this exact variant.	clinvar
BA1	Not met	Not met: the highest population allele frequency, 1.9228% in Ashkenazi Jewish, is below the 5% BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Met	Met (strong): allele frequency 1.9228% in Ashkenazi Jewish and 1.3787% in African/African American individuals is far too common for a rare cancer-predisposition disorder.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: population databases report homozygotes, but no phenotyped healthy adults confirm benignity.	gnomad_v4 gnomad_v2 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay demonstrating no damaging effect on POLD1 function or splicing was available.
BS4	Not assessed	Not assessed: no informative non-segregation evidence (affected non-carriers or unaffected carriers) was reported.
BP1	N/A	Not applicable: no missense change is present to evaluate against the gene's truncating-variant mechanism.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no co-occurrence of this variant with a pathogenic POLD1 variant was documented.
BP3	N/A	Not applicable: no protein length change in a repetitive region occurs, so there is nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI max delta 0.035 is well below the ~0.1 threshold for no predicted splicing consequence.	spliceai
BP5	Not assessed	Not assessed: no phenotype or molecular workup documenting an alternate cause was provided.
BP6	Not met	Not met: ClinVar reports no expert-panel submission for this exact variant.	clinvar
BP7	Met	Met (supporting): SpliceAI max delta 0.035 predicts no splice-site creation or disruption for this synonymous change. Flagged for human review: no nucleotide-level conservation score was available to confirm.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.