NM_002691.4:c.2041del

POLD1 · NP_002682.2:p.(Leu681SerfsTer13) · NM_002691.4

GRCh37: chr19:50912805 AC>A · GRCh38: chr19:50409548 AC>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.(Leu681SerfsTer13)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The POLD1 NM_002691.4:c.2041del (p.(Leu681SerfsTer13)) variant has been reported in ClinVar, where it is classified as uncertain significance by two clinical laboratories.

This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.00006% (1/1613242), which is well below the 0.1% rarity threshold used to support PM2.

No reviewed variant-specific functional studies were identified for this frameshift variant in the retrieved functional evidence sources.

This is a truncating frameshift variant for which the generic PVS1 framework is applicable, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.03.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	This variant is a frameshift, NM_002691.4:c.2041del, predicted to cause p.(Leu681SerfsTer13) and truncate POLD1 well upstream of the end of the coding sequence. Available gene-level evidence supports loss of function as a disease mechanism for POLD1, and the generic ClinGen SVI PVS1 framework therefore supports applying PVS1 for this truncating variant.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 applies to a different nucleotide change causing the same amino acid substitution. This variant is a frameshift, so PS1 is not applicable.
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant, so PS2 was not assessed.	clinvar
PS3	Not assessed	No well-established variant-specific functional studies demonstrating a damaging effect were identified for this frameshift variant, so PS3 was not assessed.	oncokb
PS4	Not assessed	This variant has been reported in ClinVar, but no case-control data or multiple independent affected observations sufficient to demonstrate enrichment in affected individuals were identified, so PS4 was not assessed.	clinvar
PM1	Not met	Cancer Hotspots did not identify this variant or residue as a statistically significant hotspot, so PM1 is not met.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.00006% (1/1613242), with highest population frequency 0.00008% in European non-Finnish individuals. These values are well below the 0.1% threshold typically used for rarity, supporting PM2 at supporting strength.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is used for recessive disorders with pathogenic variants observed in trans. That evidence was not relevant for this POLD1 evaluation, so PM3 is not applicable.
PM4	N/A	PM4 is intended for protein length changes caused by in-frame deletions/insertions or stop-loss variants. This variant is a frameshift and is captured by PVS1 instead, so PM4 is not applicable.	pvs1_variant_assessment
PM5	N/A	PM5 applies to a novel missense change at a residue where a different pathogenic missense change is established. This variant is a frameshift, so PM5 is not applicable.
PM6	Not assessed	No presumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not assessed.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	clinvar
PP2	N/A	PP2 is a missense-specific criterion and does not apply to this frameshift variant.
PP3	N/A	REVEL and BayesDel were not applicable because this is not a single-nucleotide missense variant, and HCI prior is not available for POLD1. SpliceAI showed a low maximum delta score of 0.03, below commonly used splicing concern thresholds, but this frameshift is already addressed through PVS1 rather than a separate PP3 call.	spliceai pvs1_variant_assessment
PP4	Not assessed	No detailed phenotype information specific enough to determine whether the clinical presentation is highly specific for a POLD1-related disorder was identified, so PP4 was not assessed.
PP5	N/A	PP5 was not used because external assertions without independently reviewable evidence are not applied in this evaluation.	clinvar
BA1	Not met	The highest observed population frequency for this variant is 0.00008% in gnomAD v4.1, which is far below the 1% threshold for BA1, so BA1 is not met.	gnomad_v4
BS1	Not met	The highest observed population frequency for this variant is 0.00008% in gnomAD v4.1, which is well below the 0.3% threshold used for BS1, so BS1 is not met.	gnomad_v4
BS2	Not met	This variant was observed only once in gnomAD v4.1 and no homozygotes were reported, which does not provide the healthy adult observations required for BS2, so BS2 is not met.	gnomad_v4
BS3	Not assessed	No well-established variant-specific functional studies showing a normal or benign effect were identified, so BS3 was not assessed.	oncokb
BS4	Not assessed	No nonsegregation data were identified for this variant, so BS4 was not assessed.	clinvar
BP1	N/A	BP1 is a missense-specific criterion and does not apply to this frameshift variant.
BP2	Not assessed	No phase data with another variant were identified, so BP2 was not assessed.
BP3	N/A	BP3 applies to in-frame variants in repetitive regions without known function. This variant is a frameshift, so BP3 is not applicable.
BP4	N/A	REVEL and BayesDel were not applicable because this is not a single-nucleotide missense variant, and HCI prior is not available for POLD1. SpliceAI predicted no significant splice impact with a maximum delta score of 0.03, but BP4 was not applied because the variant is a frameshift and computational evidence is not being used as a separate benign criterion here.	spliceai
BP5	Not assessed	No alternate molecular diagnosis explaining the phenotype was identified, so BP5 was not assessed.
BP6	N/A	BP6 was not used because external benign assertions without independently reviewable evidence are not applied in this evaluation.	clinvar
BP7	N/A	BP7 applies to synonymous or certain noncoding variants with no predicted splice impact. This variant is a coding frameshift, so BP7 is not applicable.	spliceai

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