NM_006231.4:c.6816G>A

POLE · NP_006222.2:p.(Glu2272=) · NM_006231.4

GRCh37: chr12:133201328 C>T · GRCh38: chr12:132624742 C>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting BP7 supporting benign

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Glu2272=)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_006231.4:c.6816G>A is a synonymous variant (p.Glu2272=) in exon 49 of the DNA polymerase epsilon catalytic subunit gene POLE.

This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting the PM2 criterion at supporting strength.

SpliceAI predicts no splicing impact (max delta score 0.00) for this synonymous variant located deep within exon 49, satisfying BP7 at supporting benign strength.

This variant has been reported in ClinVar as Likely benign by two clinical laboratories (Variation ID 1146301, 1-star review status, criteria provided by a single submitter).

The León-Castillo et al. 2020 custom POLE framework, which provides gene-specific rules for PM1, PS4, PP3, and BP4, applies exclusively to exonuclease-domain missense variants and does not address this synonymous variant at codon 2272, which lies outside the exonuclease domain (residues 268–471).

The variant has been observed once in somatic cancers (COSMIC COSV57678650) but has not been identified as a recurrent somatic hotspot or as a germline disease-associated variant in the literature reviewed.

Overall, the variant meets PM2 (supporting) and BP7 (supporting benign), with all other assessed criteria not met or not applicable. With one pathogenic supporting and one benign supporting criterion, the evidence is insufficient for classification as either likely pathogenic or likely benign, resulting in a Variant of Uncertain Significance (VUS).

Final determination: With PM2 (supporting) and BP7 (supporting benign) as the only met criteria, no ACMG/AMP 2015 combination threshold is satisfied for pathogenic, likely pathogenic, benign, or likely benign; the variant defaults to 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	NM_006231.4:c.6816G>A is a synonymous variant (p.Glu2272=) that does not result in a null variant (nonsense, frameshift, or canonical splice site disruption). The generic PVS1 framework does not apply to synonymous variants.	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	Synonymous variant does not alter the amino acid; PS1 requires the same amino acid change as a previously established pathogenic variant.
PS2	Not met	No de novo data available for this variant.
PS3	Not met	No functional studies have been performed on NM_006231.4:c.6816G>A. This synonymous variant at codon 2272 is outside the POLE exonuclease domain (residues 268–471) and is not represented in the León-Castillo et al. 2020 endometrial carcinoma cohorts, which focus exclusively on exonuclease-domain missense variants.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004
PS4	Not met	The custom POLE framework PS4 rule (León-Castillo et al. 2020) requires the variant to be recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count ≥10 and belong to the established pathogenic hotspot set. This synonymous variant is absent from Supplementary Table S1. Generic PS4 case-control evidence is also absent.	vcep_path_250_323_s002
PS5	N/A	Synonymous variant with no amino acid change; PS5 requires a novel missense change at a residue where a different pathogenic missense has been established.
PM1	Not met	The custom POLE framework PM1 rules apply exclusively to specific exonuclease-domain missense hotspot variants (P286R, V411L, S297F, A456P, S459F at strong; F367S, L424I, M295R, P436R, M444K, D368Y at moderate; A465V, L424V, T278M, A428T at supporting). This synonymous variant at codon 2272 is far outside the exonuclease domain (residues 268–471) and is not listed in any tier. The variant also does not lie in a statistically significant hotspot at cancerhotspots.org.	vcep_path_250_323 vcep_path_250_323_s002
PM2	Met	NM_006231.4:c.6816G>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 frequency threshold of <0.1% in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Synonymous variant with no amino acid change; PM5 requires a different missense change at the same codon. The PM5 candidate harvesting pipeline confirmed no classic same-residue candidates are available.	pm5_candidates
PM6	Not met	No de novo data available for this variant.
PP1	Not met	No segregation data available for this variant.
PP2	N/A	Synonymous variant, not a missense change. PP2 applies to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	The custom POLE framework PP3 rule requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result. This synonymous variant is absent from both tables. Under generic fallback: SpliceAI predicts no splicing impact (max delta 0.00), REVEL and BayesDel scores are not available for synonymous variants, and no multiple lines of computational evidence support a deleterious effect.	vcep_path_250_323_s003 vcep_path_250_323_s004 spliceai
PP4	Not met	No patient phenotype or family history data specific to this variant are available for assessment.
PP5	Not met	ClinVar reports this variant as Likely benign, not Pathogenic/Likely pathogenic. Additionally, the review status is 1-star (criteria provided, single submitter), which does not meet the 3-star expert panel threshold required for PP5 at supporting strength.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0%, which does not exceed the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0%, which does not exceed the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No data on observation of this variant in healthy adult controls are available.
BS3	Not met	No well-established functional studies have been performed on NM_006231.4:c.6816G>A demonstrating no damaging effect.
BS4	Not met	No segregation data are available to demonstrate lack of segregation with disease.
BP1	N/A	Synonymous variant, not a missense change. BP1 applies to missense variants in genes where primarily truncating variants cause disease.
BP2	Not met	No data on observation of this variant in trans with a pathogenic variant are available.
BP4	Not met	The custom POLE framework BP4 rule requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and ≥4 benign in silico results; this synonymous variant is absent from both tables. Under generic fallback: while SpliceAI predicts no splicing impact, additional computational evidence lines (conservation scores, REVEL/BayesDel) are unavailable for this synonymous variant. BP7 is the more specific criterion applied for the synonymous variant with no predicted splice impact.	vcep_path_250_323_s003 vcep_path_250_323_s004 spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease is available.
BP6	Not met	ClinVar reports this variant as Likely benign with a 1-star review status (criteria provided, single submitter). The 3-star expert panel threshold required for BP6 at supporting strength is not met, per the global PP5/BP6 rule requiring ClinVar 3-star expert panel status.	clinvar
BP7	Met	NM_006231.4:c.6816G>A is a synonymous variant (p.Glu2272=) located in exon 49 (42 nucleotides from the acceptor site, 1007 nucleotides from the donor site). SpliceAI predicts no splicing impact (max delta score 0.00, all delta scores at 0.00). The variant is far from splice consensus sequences and does not create a novel splice site.	spliceai

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