Variant classification summary

NM_002691.4:c.961G>A

POLD1 · NP_002682.2:p.(Gly321Ser) · NM_002691.4

GRCh37: chr19:50905989 G>A · GRCh38: chr19:50402732 G>A

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

PM1 moderate BS4 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Gly321Ser)

gnomAD AF

0.0004379252021241571 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 moderate: p.Gly321Ser lies in POLD1's critical exonuclease proofreading domain.

2

BS4 supporting: both tested sisters with endometrial cancer lacked the variant, providing non-segregation evidence.

Final determination: Under the generic ACMG/AMP 2015 fallback, one moderate pathogenic criterion plus one supporting benign criterion is insufficient to meet any definitive classification threshold, so the result remains VUS.

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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_002691.4:c.961G>A in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Gly321Ser). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no validated pathogenic or likely pathogenic comparator producing the same p.Gly321Ser amino-acid change was identified.	clinvar
PS2	Not assessed	Not assessed: no documented parental testing confirms that the POLD1 c.961G>A variant arose de novo.	PMID:30827058 PMID:33193653
PS3	Not assessed	Not assessed: the exact variant was reported, but PMID:30827058 states that no functional assay was performed and provides no measured POLD1 activity result.	PMID:25938944 PMID:30827058
PS4	Not met	Not met: the variant was observed in colorectal polyposis/cancer cases, but no control comparison or statistical enrichment estimate was reported.	PMID:25938944 PMID:30827058 PMID:33193653
PM1	Met	Met, moderate: p.Gly321Ser lies in POLD1's exonuclease domain, a critical proofreading region documented for this variant and gene.	PMID:25938944 PMID:30827058
PM2	Not met	Not met: gnomAD v3.1 non-cancer AF is 0.000250030, exceeding the generic PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: reports describe heterozygous POLD1 c.961G>A, but no pathogenic POLD1 variant in trans or biallelic affected-proband observation is documented.	PMID:30827058 PMID:25938944
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_002691.4:c.961G>A in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Gly321Ser). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no established pathogenic or likely pathogenic alternate missense change at POLD1 residue 321 was identified.	pm5_candidates
PM6	Not assessed	Not assessed: the available reports do not describe a presumed de novo POLD1 c.961G>A variant without parental testing.	PMID:30827058 PMID:33193653
PP1	Not met	Not met: one study found non-supportive segregation, with both tested sisters with endometrial cancer lacking the variant.	PMID:30827058 PMID:33193653
PP2	Not assessed	Not assessed: gene-level benign-missense rate and disease-causing missense prevalence needed for PP2 are unavailable.	PMID:25938944 PMID:30827058
PP3	Not met	Not met: missense REVEL score 0.363 is below the PP3 supporting threshold of 0.644.	revel
PP4	Not met	Not met: colorectal polyposis and cancer are nonspecific, and reported cases included alternative explanations such as MUTYH variation or MLH1 promoter hypermethylation.	PMID:25938944 PMID:30827058 PMID:33193653
PP5	Not met	Not met: exact-variant ClinVar records show no expert-panel Pathogenic or Likely pathogenic classification for NM_002691.4:c.961G>A.	clinvar
BA1	Not met	Not met: highest observed allele frequency is 0.000648145, far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: highest observed allele frequency is 0.000648145, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not assessed	Not assessed: gnomAD v4.1 reports one homozygote, but no individual phenotype or disease-status information establishes the BS2 healthy-person requirement.	gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: no validated assay demonstrates normal POLD1 function, and PMID:30827058 explicitly states that no functional assay was performed.	PMID:25938944 PMID:30827058
BS4	Met	Met, supporting: both tested sisters with endometrial cancer lacked POLD1 c.961G>A, providing non-segregation evidence.	PMID:30827058
BP1	Not met	Not met: POLD1 disease-relevant evidence centers on exonuclease-domain missense variants, not a truncating-predominant mechanism.	PMID:25938944 PMID:30827058
BP2	Not assessed	Not assessed: a reported heterozygous MUTYH variant lacked phase information, and no qualifying pathogenic POLD1 co-occurrence in cis or trans was documented.	PMID:30827058 PMID:25938944
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_002691.4:c.961G>A in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Gly321Ser). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.363 exceeds the BP4 supporting threshold of 0.29.	revel
BP5	Not met	Not met: alternative MUTYH or MLH1-related findings were reported, but neither is sufficiently established here as the confirmed explanation for the full phenotype.	PMID:30827058
BP6	Not met	Not met: exact-variant ClinVar contains single-submitter Likely benign assertions but no expert-panel Benign or Likely benign classification.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002691.4:c.961G>A in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Gly321Ser). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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