NM_006231.4:c.1871A>C

POLE · NP_006222.2:p.(His624Pro) · NM_006231.4

GRCh37: chr12:133245449 T>G · GRCh38: chr12:132668863 T>G

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(His624Pro)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_006231.4:c.1871A>C (p.His624Pro) is a missense variant in exon 19 of POLE, located in the C-terminal polymerase domain outside the exonuclease domain (residues ~268–471) where established pathogenic hotspot variants cluster.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, comprising over 300,000 population alleles without observation (PM2_Supporting).

The variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp Genetics, SCV001206773), and no additional submissions from expert panels are available.

The León-Castillo et al. 2020 custom POLE framework does not assign PM1, PS4, PP3, or BP4 to this variant, as p.His624Pro is absent from all supplementary tables (S1, S2, S3) and is not among the established exonuclease-domain hotspot or recurrent variants.

Computational analyses are equivocal: REVEL score 0.712 is borderline; BayesDel score 0.151 is modest; SpliceAI predicts no splicing impact (max delta 0.01). These do not meet thresholds for PP3 or BP4 under either the custom or generic frameworks.

No variant-specific functional studies, segregation data, de novo observations, case-control enrichment, or phenotype specificity data were identified in the literature or public databases.

With only PM2_Supporting met, this variant does not reach the threshold for Likely Pathogenic (requires ≥2 Supporting with at least PVS1, or 1 Moderate + 4 Supporting, etc.) or Likely Benign (requires ≥2 Supporting benign). The variant remains classified as a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 combination rules.

Final determination: Under ACMG/AMP 2015 final combination rules (adopted by the León-Castillo 2020 custom POLE framework), a single supporting criterion (PM2_Supporting) is insufficient to classify the variant as Likely Pathogenic or Likely Benign, resulting in 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
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. NM_006231.4:c.1871A>C is a missense substitution, not an in-frame indel.
PM3	N/A	PM3 applies to variants observed in trans with a pathogenic variant in recessive disorders. POLE-associated disease is not established as recessive, and no recessive inheritance context is available for this variant.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants. NM_006231.4:c.1871A>C is a missense substitution, not an in-frame indel or stop-loss.
PVS1	N/A	NM_006231.4:c.1871A>C is a missense variant (p.His624Pro). It does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The generic PVS1 framework is not applicable to this variant class.	pvs1_generic_framework
PS1	Not met	No evidence of a different nucleotide change at codon 624 resulting in the same amino acid substitution (p.His624Pro) that has been previously classified as pathogenic.
PS2	Not met	No de novo occurrence data available for this variant. PS2 requires a confirmed de novo observation with both maternity and paternity confirmed.
PS3	Not met	No variant-specific functional evidence was identified. OncoKB classifies this variant as Unknown Oncogenic Effect. No publications were found reporting functional characterization of NM_006231.4:c.1871A>C (p.His624Pro).	oncokb
PS4	Not met	The POLE custom framework (León-Castillo 2020) restricts PS4_Supporting to exact established pathogenic hotspot variants (P286R, V411L, A456P, S297F) that are recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with combined EC count ≥10. p.His624Pro is not among these variants and is absent from Supplementary Table S1. No germline case-control data are available. PS4 is not met.	vcep_path_250_323_s002 vcep_path_250_323
PS5	Not met	No reputable source has recently reported this variant as pathogenic. ClinVar classification is Uncertain significance (single submitter).	clinvar
PM1	Not met	p.His624Pro is located at residue 624 in the C-terminal polymerase domain of POLE, outside the exonuclease domain (residues ~268–471) where established pathogenic hotspot variants cluster. The León-Castillo 2020 custom framework limits PM1 to exact exonuclease-domain hotspot variants listed in the paper and Supplementary Table S1; p.His624Pro is not among them. No evidence of a statistically significant mutational hotspot at this residue.	vcep_path_250_323_s002 vcep_path_250_323 vcep_path_250_323_s003 vcep_path_250_323_s004
PM2	Met	NM_006231.4:c.1871A>C (p.His624Pro) is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), comprising a total population of over 300,000 alleles without observation. This supports a pathogenic role for a rare missense variant in a gene where pathogenic variants are established.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No same-residue (codon 624) comparator missense variant with a different amino acid change has been identified as pathogenic or likely pathogenic. Automated PM5 candidate harvesting could not confirm classic same-residue semantics. PM5 cannot be applied.
PM6	Not met	No de novo observation has been reported for this variant. PM6 requires a confirmed de novo event with both maternity and paternity confirmed, or a confirmed de novo with an unconfirmed parental relationship at a lower strength.
PP1	Not met	No segregation data are available for this variant. PP1 requires cosegregation of the variant with disease in multiple affected family members.
PP2	Not met	No HCI prior probability score is available for POLE. PP2 requires a demonstrated low rate of benign missense variation in the gene and evidence that missense variants are a common disease mechanism. While POLE exonuclease-domain missense variants are an established pathogenic mechanism, the HCI metric cannot be evaluated for this specific variant, and the variant lies outside the exonuclease domain where pathogenic missense variants are concentrated.
PP3	Not met	p.His624Pro is not present in the León-Castillo supplementary in silico tables (S2 or S3), so the custom PP3 rule does not apply. Under generic in silico assessment: REVEL score 0.712 is borderline and does not clearly exceed established pathogenic thresholds; BayesDel score 0.151 is modest; SpliceAI max delta score 0.01 predicts no splicing impact. Multiple lines of computational evidence do not convincingly support a deleterious effect.	revel bayesdel spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
PP4	Not met	No information is available regarding the clinical phenotype or specificity of presentation for this variant. PP4 requires the variant to be observed in a patient whose phenotype or family history is highly specific for the disease associated with the gene.
PP5	Not met	No reputable source has recently reported this variant as pathogenic. ClinVar classification is Uncertain significance (criteria provided, single submitter).	clinvar
BA1	Not met	NM_006231.4:c.1871A>C is absent from all gnomAD population databases (v2.1, v4.1, Canada). The allele frequency is 0%, well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_006231.4:c.1871A>C is absent from all gnomAD population databases. The allele frequency is 0%, well below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available regarding observation of this variant in healthy adult individuals in a context that would support a benign classification. BS2 requires observation in trans with a pathogenic variant or in a healthy adult for a fully penetrant dominant disorder.
BS3	Not met	No functional evidence demonstrating a neutral or benign effect has been identified for this variant. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional data.	oncokb
BS4	Not met	No segregation data are available for this variant. BS4 requires lack of cosegregation with disease in affected family members.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. POLE has well-established pathogenic missense variants in the exonuclease domain (P286R, V411L, S297F, A456P, S459F), indicating that missense changes are a recognized disease mechanism for this gene. Therefore BP1 does not apply.	vcep_path_250_323
BP2	Not met	No data are available regarding observation of this variant in trans with a known pathogenic variant in POLE. BP2 requires observation in trans with a pathogenic dominant variant or in cis with a pathogenic variant in a recessive disorder.
BP4	Not met	p.His624Pro is not present in the León-Castillo supplementary in silico tables (S2 or S3), so the custom BP4 rule does not apply. Under generic in silico assessment: SpliceAI predicts no splicing impact (max delta 0.01); REVEL score 0.712 is borderline; BayesDel score 0.151 does not indicate a benign profile. Multiple lines of computational evidence do not clearly suggest no impact on the gene product.	revel bayesdel spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
BP5	Not met	No evidence of an alternate molecular basis for disease has been identified in individuals carrying this variant. BP5 requires the variant to be found in a case with an alternate molecular basis for disease.
BP6	Not met	No reputable source has reported this variant as benign or likely benign. ClinVar classification is Uncertain significance (single submitter).	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. NM_006231.4:c.1871A>C is a missense substitution (p.His624Pro), not a synonymous variant.

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