NM_006231.4:c.3386A>G

POLE · NP_006222.2:p.(Asp1129Gly) · NM_006231.4

GRCh37: chr12:133234008 T>C · GRCh38: chr12:132657422 T>C

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Asp1129Gly)

gnomAD AF

2.478394595117067e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_006231.4:c.3386A>G (p.Asp1129Gly) in POLE is a rare missense variant with an allele frequency of 0.00025% in gnomAD v4.1 (4/1,613,948 alleles, 0 homozygotes), meeting PM2 at supporting strength.

This variant is absent from gnomAD v2.1 and has a grpmax filtering allele frequency of 7.9e-07, consistent with a rare variant.

The variant has been reported as Uncertain significance in ClinVar (VariationID 934060) by a single clinical laboratory (Labcorp Genetics, SCV001373503).

This variant has previously been reported in somatic cancers (COSMIC COSV57675934, n=1).

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

The variant is absent from the León-Castillo et al. 2020 supplementary tables of recurrent POLE endometrial carcinoma variants and does not map to any of the five established exonuclease-domain hotspot positions (P286R, V411L, S297F, A456P, S459F).

In silico predictions are conflicting: REVEL score of 0.797 is in the deleterious range but BayesDel score of 0.157532 is in the benign range, and HCI prior is not available, precluding application of PP3 or BP4.

OncoKB did not identify variant-specific reviewed functional evidence for p.Asp1129Gly.

Overall, only one supporting-level pathogenic criterion (PM2) is met. No benign criteria are met. The evidence is insufficient for a classification beyond Variant of Uncertain Significance under the custom POLE framework (León-Castillo et al. 2020).

Final determination: Standard ACMG/AMP 2015 combination rules: with only 1 supporting criterion met (PM2) and zero criteria at very strong, strong, moderate, or benign levels, no pathogenic, likely pathogenic, benign, or likely benign combination is satisfied, defaulting to 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	N/A	This is a missense variant (p.Asp1129Gly) and does not fall into the default PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants.	pvs1_variant_assessment
PS1	Not met	No evidence was identified for a different nucleotide change at codon 1129 resulting in the same amino acid substitution (p.Asp1129Gly) with an established pathogenic classification.	clinvar
PS2	Not assessed	No de novo data are available for this variant.
PS3	Not met	No variant-specific functional studies were identified for p.Asp1129Gly. The variant lies outside the POLE exonuclease domain (residues 268–471). OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No publications in the case literature packet contain functional data for this variant.	oncokb vcep_path_250_323
PS4	Not met	The León-Castillo custom POLE framework limits PS4_Supporting to four specific hotspot variants (p.P286R, p.V411L, p.A456P, p.S297F). p.Asp1129Gly is not among these. Under generic ACMG, a single COSMIC somatic observation (n=1) does not meet PS4 thresholds for statistically significant enrichment in affected individuals.	vcep_path_250_323_s002
PS5	Not met	No established pathogenic variant at codon 1129 was identified from ClinVar or the literature. No comparator variant at this codon is available to support PS5.	clinvar
PM1	Not met	p.Asp1129 is located at position 1129, well outside the POLE exonuclease domain (residues 268–471). The León-Castillo custom framework assigns PM1 only to specific listed hotspot variants within the exonuclease domain. The position is not in a statistically significant hotspot per cancerhotspots.org. No critical functional domain has been characterized at this C-terminal region.	vcep_path_250_323_s002 vcep_path_250_323
PM2	Met	This variant is absent from gnomAD v2.1 and extremely rare in gnomAD v4.1 (AF=2.48e-06, 4/1,613,948 alleles, no homozygotes). The allele frequency of 0.00025% is well below the 0.1% PM2 threshold. grpmax FAF is 7.9e-07.	gnomad_v2 gnomad_v4
PM5	Not met	No comparator variant at codon 1129 with a different missense change and an established pathogenic classification was identified. The automated PM5 candidate search found zero candidates.	pm5_candidates
PM6	Not assessed	No de novo data are available for this variant.
PP1	Not assessed	No cosegregation data are available for this variant.
PP2	Not met	PP2 requires a missense variant in a gene where missense variants are a common disease mechanism and benign missense variation is rare. POLE is a large gene with many missense variants. The León-Castillo framework does not provide a gene-specific PP2 rule, and under generic ACMG criteria, this variant does not meet PP2 requirements.
PP3	Not met	The variant is absent from Supplementary Tables S2 and S3, so the custom POLE PP3 rule does not apply. Under generic ACMG, multiple lines of in silico evidence must support a deleterious effect. REVEL score of 0.797 is in the deleterious range, but BayesDel score of 0.157532 is in the benign range, and SpliceAI predicts no splicing impact (max delta 0.02). The conflicting in silico predictions do not satisfy the requirement for multiple lines of computational evidence supporting a deleterious effect.	revel bayesdel spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
PP4	Not assessed	No phenotype or family history data specific to the proband are available.
PP5	Not met	ClinVar reports this variant as Uncertain significance with a review status of criteria provided, single submitter (1-star). PP5 requires a 3-star expert panel classification as pathogenic; a single-submitter VUS classification does not meet this threshold.	clinvar
BA1	Not met	The allele frequency in gnomAD v4.1 is 0.00025% (AF=2.48e-06), far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	The allele frequency of 0.00025% is well below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not met	No homozygotes have been observed in gnomAD v2.1 or v4.1. BS2 requires observation in a healthy adult homozygous state.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no deleterious effect were identified for this variant.
BS4	Not assessed	No cosegregation data are available to assess lack of segregation with disease.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where only truncating variants are known to cause disease. POLE has well-established pathogenic missense variants within the exonuclease domain (e.g., P286R, V411L, S297F, A456P, S459F), so this criterion does not apply.	vcep_path_250_323
BP2	Not assessed	No data on observations in trans with a pathogenic variant are available.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions; this is a missense substitution.
BP4	Not met	BP4 requires multiple lines of in silico evidence predicting no impact. The variant is absent from Supplementary Tables S2 and S3, so the custom BP4 rule does not apply. Under generic ACMG, REVEL score of 0.797 is in the deleterious range, contradicting a benign in silico prediction. Multiple predictors do not converge on a benign call.	revel bayesdel spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
BP5	Not assessed	No information about an alternative molecular cause of disease in the proband is available.
BP6	Not met	ClinVar reports this variant as Uncertain significance, not benign. BP6 requires a reputable source (3-star expert panel) to classify the variant as benign. A single-submitter VUS classification does not meet this threshold.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is a missense substitution (p.Asp1129Gly).

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.