Variant classification summary

NM_002691.4:c.2959del

POLD1 · NP_002682.2:p.(Asp987ThrfsTer58) · NM_002691.4

GRCh37: chr19:50919865 AG>A · GRCh38: chr19:50416608 AG>A

Gene: POLD1 Transcript: NM_002691.4

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Asp987ThrfsTer58)

gnomAD AF

5.7738350325515986e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): frameshift p.(Asp987ThrfsTer58) introduces a premature stop 58 codons downstream, predicted to trigger nonsense-mediated decay.

2

PM2 (Supporting): overall allele frequency 5.77e-06 in gnomAD v4.1, far below the 0.1% threshold, with no homozygotes.

3

Overall: Likely Pathogenic — PVS1 (Very Strong) plus PM2 (Supporting) under the ClinGen SVI 2020 PM2-downgrade addendum (PVS1 + 1 supporting).

Final determination: PVS1 (very strong) + PM2 (supporting) combine to Likely Pathogenic per the ClinGen SVI 2020 PM2-downgrade addendum.

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	Met	Met (Very Strong): frameshift creates a premature stop codon 58 codons downstream, predicted to trigger nonsense-mediated decay.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework clinvar
PS1	N/A	Not applicable: frameshift produces no altered amino acid, so there is no residue to compare against a previously established pathogenic change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental testing or de novo confirmation for this variant was documented.
PS3	Not assessed	Not assessed: no functional assay data for this exact variant was available.
PS4	Not assessed	Not assessed: no case-control counts or qualifying case series for this exact variant were available.	PMID:23263490 PMID:23447401
PM1	N/A	Not applicable: PM1 requires a missense variant; this frameshift leaves no altered residue to evaluate for hotspot membership.	generic_acmg_combination_rules
PM2	Met	Met (Supporting): allele frequency 5.77e-06 in gnomAD v4.1, far below the 0.1% threshold. Flagged for human review: a ClinVar submitter noted gnomAD frequency data at this position may be unreliable.	gnomad_v4 gnomad_v2 gnomad_canada clinvar
PM3	N/A	Not applicable: POLD1 disease here is dominant, with no evidence of a recessive disorder requiring trans configuration.
PM4	N/A	Not applicable: PM4 applies to in-frame indels or stop-loss changes; this frameshift causes no protein length change.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense change at this residue; this frameshift creates no missense to compare.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no parental testing or clinical context supporting an assumed de novo occurrence was documented.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or segregation data for this variant were documented.
PP2	N/A	Not applicable: PP2 applies only to missense variants; this frameshift involves no missense change.	generic_acmg_combination_rules
PP3	N/A	Not applicable: PP3 concerns missense/synonymous splicing predictions; no in-silico scores apply to this frameshift.
PP4	Not assessed	Not assessed: no patient-level phenotype or family-history data specific to this case was available.
PP5	Not met	Not met: ClinVar variation 935838 has only two Uncertain-significance laboratory submissions and no expert-panel classification.	clinvar
BA1	Not met	Not met: highest observed allele frequency 5.53e-05 is far below the 1% BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: highest observed allele frequency 5.53e-05 is far below the 0.3% BS1 threshold.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no phenotype-confirmed healthy-adult observation exists; zero homozygotes alone are insufficient.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no functional assay data for this variant was available to demonstrate normal function.
BS4	Not assessed	Not assessed: no tested relatives or non-segregation observations were documented for this variant.
BP1	N/A	Not applicable: BP1 applies only to missense variants; this frameshift involves no missense change.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no data on phase with another variant (trans or cis) was available.
BP3	N/A	Not applicable: BP3 concerns in-frame indels in repetitive regions; this frameshift does not qualify.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: BP4 requires missense/synonymous in-silico scores; none apply to this frameshift.
BP5	Not assessed	Not assessed: no alternative molecular cause for the patient's phenotype was documented.
BP6	Not met	Not met: ClinVar variation 935838 has only two Uncertain-significance laboratory submissions and no expert-panel classification.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants; this frameshift alters the encoded protein sequence.	generic_acmg_combination_rules

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