NM_002691.4:c.2716_2717del

POLD1 · NP_002682.2:p.(Arg906AspfsTer47) · NM_002691.4

GRCh37: chr19:50918842 CGA>C · GRCh38: chr19:50415585 CGA>C

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Arg906AspfsTer47)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002691.4:c.2716_2717del (NP_002682.2:p.(Arg906AspfsTer47)) is a frameshift variant in exon 21 of 27 coding exons of POLD1. The deletion is predicted to cause a premature termination codon subject to nonsense-mediated decay, meeting PVS1 at very strong strength under the ClinGen SVI framework (PMC6185798). POLD1 loss of function is an established germline disease mechanism for polymerase proofreading-associated polyposis and cancer predisposition.

The variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency 0.00%), meeting PM2 at supporting strength under generic ACMG/AMP 2015 criteria (threshold <0.1%).

No additional pathogenic criteria are met. The variant is absent from ClinVar, has no published functional data, no de novo reports, no segregation data, and no case-control evidence. SpliceAI predicts no splice impact (max delta = 0.04). OncoKB shows Unknown Oncogenic Effect. No cancerhotspots.org hotspot at this residue. No benign criteria are met.

Under the generic ACMG/AMP 2015 combination rules (PMID:25741868), PVS1 (very strong) with only one supporting criterion (PM2) does not formally reach the Likely Pathogenic threshold (requires 1 very strong + 1 moderate, or 1 strong + 1-2 moderate, etc.). However, a frameshift variant in a known tumor suppressor gene, absent from all population databases, is strongly indicative of pathogenicity. Many clinical laboratories would classify this as Likely Pathogenic using professional judgment. Formal classification under the strict combination rules is Variant of Uncertain Significance (VUS).

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	Met	NM_002691.4:c.2716_2717del is a frameshift variant in exon 21 of 27 coding exons, predicted to cause a premature termination codon (NP_002682.2:p.(Arg906AspfsTer47)) subject to nonsense-mediated decay. POLD1 loss of function is an established germline disease mechanism supported by literature evidence for polymerase proofreading-associated polyposis (PPAP) and cancer predisposition. The variant meets PVS1 at full strength under the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 requires the same amino acid change produced by a different nucleotide change. This variant is a 2bp deletion (frameshift), not a single nucleotide substitution.
PS2	Not met	No de novo data are available for this variant. No publications or ClinVar submissions report de novo occurrence.
PS3	Not met	No variant-specific functional data are available. OncoKB classifies this variant as Unknown Oncogenic Effect. No publications with functional characterization of NM_002691.4:c.2716_2717del were identified.
PS4	Not met	No case-control or cohort data available. The variant is absent from ClinVar (zero submissions) and has not been reported in any publication.
PS5	N/A	PS5 (revised ACMG/AMP 2024) applies to variants with strong functional evidence functionally equivalent to established pathogenic variants. No such data exist for this variant; no related pathogenic comparator was identified.
PM1	Not met	The variant lies at codon 906 in the C-terminal region of POLD1, which is part of the polymerase domain. However, no variant-specific or domain-specific functional data are citeable from the case materials to confirm this region is a well-established critical functional domain without benign variation. Cancerhotspots.org shows no statistically significant hotspot at this residue.
PM2	Met	NM_002691.4:c.2716_2717del is completely absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency 0.00%), far below the generic ACMG PM2 threshold of <0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	Not met	PM4 applies to protein length changes from in-frame deletions/insertions in non-repeat regions or stop-loss variants. This variant is a frameshift truncation, which is assessed under PVS1 rather than PM4.
PM5	N/A	PM5 requires a different missense variant at the same amino acid residue classified as pathogenic. This variant is a frameshift deletion, not a missense change. Automated PM5 candidate harvesting confirmed not applicable — no same-residue missense comparators exist.
PM6	Not met	No de novo data are available. No publications or ClinVar submissions report de novo occurrence of this variant.
PP1	Not met	No segregation data are available. No family studies or co-segregation analyses have been reported for this variant.
PP2	N/A	PP2 applies to missense variants in genes where missense is a common disease mechanism and benign missense variation is rare. This variant is a frameshift, not a missense.
PP3	Not met	Multiple in silico tools predict no significant effect. SpliceAI predicts no splice impact (max delta score = 0.04, well below the 0.1 threshold). REVEL and BayesDel scores are unavailable (not an SNV). HCI prior not available for this gene. No in silico evidence supports a deleterious effect.	spliceai
PP4	Not met	No patient phenotype or clinical data are available in the case materials to assess phenotype specificity or fit.
PP5	Not met	The variant is absent from ClinVar — it has not been submitted by any laboratory and has no expert panel classification. No reputable source has classified this variant as pathogenic.
BA1	Not met	The variant is absent from gnomAD (allele frequency 0.00%), far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD (allele frequency 0.00%), far below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No observations in healthy adults or co-occurrence data are available. The variant is absent from population databases, precluding BS2 application.
BS3	Not met	No functional studies demonstrating no deleterious effect are available for this variant.
BS4	Not met	No segregation data are available to assess lack of co-segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant is itself a truncating (frameshift) variant.
BP2	Not met	No data on co-occurrence with a known pathogenic variant in trans are available.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This variant is an out-of-frame (frameshift) deletion.
BP4	Not met	Multiple in silico tools predict no significant effect. SpliceAI predicts no splice impact (max delta = 0.04). However, the absence of a damaging prediction does not constitute positive evidence of a benign effect for a frameshift variant — BP4 requires positive computational evidence supporting a benign interpretation, not merely absence of pathogenic signal.	spliceai
BP5	Not met	No data indicate this variant is found in a case with an alternative molecular basis for disease.
BP6	Not met	The variant is absent from ClinVar — no reputable source has classified it as benign.
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. This variant is a 2bp frameshift deletion.

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.