NM_006231.4:c.4411C>T

POLE · NP_006222.2:p.(Arg1471Cys) · NM_006231.4

GRCh37: chr12:133220026 G>A · GRCh38: chr12:132643440 G>A

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Arg1471Cys)

gnomAD AF

2.5399232571480254e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_006231.4:c.4411C>T (p.Arg1471Cys) is a missense variant in the C-terminal polymerase domain of POLE, outside the exonuclease domain (residues ~268-471).

This variant is present at very low frequency in gnomAD: v2.1 AF=0.00835% (21/251,470 alleles) and v4.1 AF=0.00254% (41/1,614,222 alleles), with zero homozygotes in either dataset (PM2_Supporting).

The variant is absent from all León-Castillo et al. 2020 supplementary tables (S1, S2, S3) and is not one of the five established pathogenic exonuclease-domain hotspots (P286R, V411L, S297F, A456P, S459F).

Computational predictions are mixed: REVEL 0.334 (borderline, below pathogenic threshold of 0.5), BayesDel 0.016 (benign range), SpliceAI max delta 0.01 (no predicted splicing impact). These do not support a deleterious effect per PP3 or a benign effect per BP4.

Five publications were cited by ClinVar submitters or identified in literature review. Full-text review confirmed none mention NM_006231.4:c.4411C>T or p.Arg1471Cys.

ClinVar reports this variant as Uncertain significance (VariationID 240513, 7 clinical laboratories, criteria provided single submitter). No expert panel review has been conducted.

This variant has been reported in COSMIC (COSV57693254, n=5 somatic occurrences), but somatic recurrence does not provide germline pathogenicity evidence.

Total evidence: PM2_Supporting (1 supporting pathogenic criterion). No benign criteria met. Classification remains Uncertain Significance.

Final determination: A single PM2_Supporting criterion does not meet any Pathogenic or Likely Pathogenic combination threshold under ACMG/AMP 2015 rules (PMID:25741868); the default classification for evidence insufficient to reach Likely Pathogenic or Likely Benign is 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	NM_006231.4:c.4411C>T is a missense variant (p.Arg1471Cys) and does not fall into the default PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Generic PVS1 framework is not applicable per pvs1_variant_assessment.	pvs1_generic_framework
PS1	Not met	No known pathogenic variant with the same amino acid change (p.Arg1471Cys) has been identified in ClinVar or the literature. Variant is classified as VUS by all 7 ClinVar submitters.	clinvar
PS2	Not met	No documented de novo occurrence for NM_006231.4:c.4411C>T was identified in the literature or ClinVar submissions.
PS3	Not met	No variant-specific functional data or systematic range characterization including position 1471 was identified. The variant lies outside the exonuclease domain (residues ~268-471) in the C-terminal polymerase region. No full-text publication mentioned this variant or functionally characterized the region spanning codon 1471.
PS4	Not met	The León-Castillo et al. 2020 custom PS4 rule only applies to the five established hotspot variants (P286R, V411L, A456P, S297F) with combined EC count ≥10 in Supplementary Table S1. p.Arg1471Cys is absent from Table S1 and does not meet the custom framework criteria. No germline case-control data is available for this variant.	vcep_path_250_323_s002 clinvar
PS5	Not met	No evidence to support PS5 application. No alternative established pathogenic variant or additional pathogenic evidence streams were identified for this variant.
PM1	Not met	The León-Castillo et al. 2020 custom PM1 rules apply to specific exonuclease-domain hotspot and recurrent missense variants (P286R, V411L, S297F, A456P, S459F at Strong; F367S, L424I, M295R, P436R, M444K, D368Y at Moderate; A465V, L424V, T278M, A428T at Supporting). p.Arg1471Cys is not among these variants. Additionally, position 1471 is in the C-terminal polymerase domain, far outside the exonuclease domain (residues ~268-471). No alternative well-characterized functional domain encompasses position 1471.	vcep_path_250_323_s002 vcep_path_250_323
PM2	Met	This variant is present at very low frequency in population databases: gnomAD v2.1 AF=0.00835% (21/251,470 alleles, 0 homozygotes) and gnomAD v4.1 AF=0.00254% (41/1,614,222 alleles, 0 homozygotes). Highest subpopulation frequency is East Asian at 0.043% (v2.1). Allele frequency is well below the 0.1% threshold for PM2, but the variant is not absent from population databases.	gnomad_v2 gnomad_v4
PM5	Not met	No same-residue comparator variants with pathogenic or likely pathogenic classification were identified. The pm5_candidates search returned zero candidates.	pm5_candidates
PM6	Not met	No de novo occurrence of NM_006231.4:c.4411C>T was documented in any reviewed publication or ClinVar submission.
PP1	Not met	Although one ClinVar submitter (Invitae SCV000289377) asserted PP1 citing PMIDs 30093976 and 34897210, full-text review of PMID:30093976 confirmed the paper does not mention POLE or this variant. PMID:34897210 full text was unavailable for verification. No confirmed cosegregation data exists for this variant.
PP2	Not met	POLE is a large gene with considerable benign missense variation in population databases. While certain missense variants in the exonuclease domain are pathogenic, PP2 requires a low rate of benign missense variation across the gene, which is not established for POLE outside the exonuclease domain.	gnomad_v2 gnomad_v4
PP3	Not met	The León-Castillo et al. 2020 custom PP3 rule requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico results. p.Arg1471Cys is absent from both Tables S2 and S3. Generic in silico assessment: REVEL 0.334 is below the pathogenic threshold (typically 0.5); BayesDel 0.016 is in the benign range; SpliceAI max delta 0.01 predicts no splicing impact. The computational evidence does not support a deleterious effect.	vcep_path_250_323_s003 vcep_path_250_323_s004 revel bayesdel spliceai
PP4	Not met	No patient-specific phenotype or clinical information was provided to assess whether the variant explains a highly specific phenotype. The variant has been observed in individuals undergoing hereditary cancer testing, but clinical details are not available.
PP5	Not met	ClinVar classification is 'Uncertain significance' with review status 'criteria provided, single submitter' (7 clinical laboratories). This does not meet the 3-star expert panel threshold required for PP5 application. No reputable source has classified this variant as pathogenic.	clinvar
BA1	Not met	gnomAD v2.1 allele frequency is 0.00835% and v4.1 is 0.00254%, both far below the >1% threshold required for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD v2.1 allele frequency is 0.00835% and v4.1 is 0.00254%, both below the >0.3% threshold for BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations in gnomAD (0 homozygotes across v2.1 and v4.1 combined). POLE-associated disease is autosomal dominant; observation in trans with a pathogenic variant would not apply. No healthy adult homozygous data available.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating a neutral effect for this variant or a systematic range including position 1471 were identified in the literature. Absence of functional data does not constitute benign functional evidence.
BS4	Not met	No segregation data is available to assess lack of cosegregation with disease. The variant has been observed in individuals with suspected hereditary cancer syndromes, but no family studies demonstrate non-segregation.
BP1	Not met	BP1 applies when a missense variant is found in a gene where only truncating variants cause disease. POLE has established pathogenic missense variants, particularly in the exonuclease domain (P286R, V411L, S297F, A456P, S459F), indicating that missense is a known disease mechanism. Even though p.Arg1471Cys lies outside the exonuclease domain, BP1 is not appropriate for this gene.	vcep_path_250_323
BP2	Not met	No observation of this variant in trans with a known pathogenic POLE variant or in a homozygous state. gnomAD reports 0 homozygotes.	gnomad_v2 gnomad_v4
BP4	Not met	The León-Castillo et al. 2020 custom BP4 rule requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and ≥4 benign in silico results. p.Arg1471Cys is absent from both tables. Generic assessment: REVEL 0.334 is borderline (neither clearly pathogenic >0.5 nor clearly benign <0.2); BayesDel 0.016 is in the benign range; SpliceAI delta 0.01 predicts no splicing impact. The computational evidence is mixed and does not provide multiple lines unequivocally supporting a benign impact.	vcep_path_250_323_s003 vcep_path_250_323_s004 revel bayesdel spliceai
BP5	Not met	No evidence that variants in POLE cause a disease distinct from the patient's phenotype. POLE is associated with hereditary colorectal cancer and polyposis syndromes, consistent with the clinical context in which this variant has been observed.
BP6	Not met	ClinVar classification is 'Uncertain significance' (7 clinical laboratories). No reputable source has classified this variant as benign. The review status 'criteria provided, single submitter' does not meet the 3-star expert panel threshold required for BP6 application.	clinvar
BP7	N/A	NM_006231.4:c.4411C>T is a missense variant (p.Arg1471Cys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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.