NM_006231.4:c.-11C>T

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133263912 G>A · GRCh38: chr12:132687326 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.?

gnomAD AF

2.002584669279817e-06 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_006231.4:c.-11C>T is a non-coding promoter/5'UTR substitution 11 bases upstream of the ATG start codon. It is present at extremely low frequency in gnomAD v4.1 (3/1,498,064 alleles, AF 0.00020%, all South Asian) and absent from gnomAD v2.1 and gnomAD-Canada, meeting PM2 at supporting level.

PVS1 does not apply as this is a non-coding variant and not a null variant. The León-Castillo 2020 custom POLE framework criteria (PM1, PS4, PP3, BP4) apply only to exonuclease-domain missense variants and do not extend to this promoter variant.

SpliceAI predicts no splice impact (max delta 0.00). No functional studies, segregation data, de novo reports, case-control data, or ClinVar classifications are available for this variant.

No publications specifically mention NM_006231.4:c.-11C>T. Five papers reviewed in the PVS1 gene context support POLE loss-of-function as a germline disease mechanism at the gene level but do not report this specific variant.

With only PM2_Supporting met, this variant does not meet any ACMG/AMP 2015 classification threshold (requires ≥2 pathogenic supporting criteria with additional evidence, or BS1/BA1 thresholds for benign classification). The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: A single supporting criterion does not satisfy any ACMG/AMP 2015 classification threshold; variants default to VUS when no pathogenic or benign combination rule is satisfied.

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	Not met	NM_006231.4:c.-11C>T is a promoter/5'UTR substitution 11 bases upstream of the ATG start codon. PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus). The ClinGen SVI PVS1 framework does not apply to non-coding promoter variants, and the pvs1_variant_assessment confirms 'apply_generic_pvs1_framework: false' with variant_bucket 'other'.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	Non-coding variant; no amino acid change to compare with alternative nucleotide changes.
PS2	Not met	No de novo data available for NM_006231.4:c.-11C>T. The variant is absent from ClinVar and no publications report de novo observations.
PS3	Not met	No functional studies are available for NM_006231.4:c.-11C>T. In silico tools (REVEL, BayesDel) do not score non-coding variants; SpliceAI predicts no splice impact (max delta 0.00). No well-established in vitro or in vivo functional assays have been performed for this variant.	spliceai
PS4	Not met	The León-Castillo 2020 custom POLE PS4 framework applies only to exonuclease-domain missense variants recurrent in COSMIC/TCGA endometrial carcinoma cohorts. NM_006231.4:c.-11C>T is a non-coding promoter variant, absent from COSMIC, and not represented in the León-Castillo supplementary recurrence tables. No germline case-control enrichment data are available.	vcep_path_250_323_s002
PS5	Not met	No ClinVar submissions, no expert panel classifications, and no publications report NM_006231.4:c.-11C>T as a pathogenic variant.	clinvar
PM1	Not met	The León-Castillo 2020 custom POLE PM1 framework assigns PM1 only to specific exonuclease-domain missense variants (e.g., P286R, V411L, S297F, A456P, S459F at strong; F367S, L424I at moderate; A465V, L424V at supporting). NM_006231.4:c.-11C>T is a non-coding promoter variant — it is not a missense variant, is not within the exonuclease domain, and is absent from the supplementary tables. The generic ACMG/AMP PM1 also does not apply: the c.-11 5'UTR position is not an established mutational hotspot or critical functional domain without benign variation for POLE.	vcep_path_250_323 vcep_path_250_323_s002
PM2	Met	NM_006231.4:c.-11C>T is present at extremely low frequency in population databases. gnomAD v4.1 reports 3 alleles out of 1,498,064 (AF 2.0e-06, 0.00020%), all in the South Asian subpopulation (SAS AF 3.75e-05). The variant is absent from gnomAD v2.1 and gnomAD-Canada. The total allele frequency is well below the 0.1% PM2 threshold, consistent with absence from controls at sufficient depth.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Non-coding variant does not alter an amino acid residue, so a same-residue pathogenic comparator cannot exist. pm5_candidates.json confirms PM5 is not applicable.	pm5_candidates
PM6	Not met	No de novo evidence is available for NM_006231.4:c.-11C>T. No publications report a de novo observation with confirmed maternity and paternity.
PP1	Not met	No segregation data are available for NM_006231.4:c.-11C>T. No family studies or co-segregation analyses have been reported.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism. NM_006231.4:c.-11C>T is a non-coding promoter variant, not a missense change. Even if POLE has a low rate of benign missense variation, this criterion is restricted to missense variants.
PP3	Not met	The León-Castillo 2020 custom PP3 rule requires the variant to be a missense variant present in Supplementary Tables S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result. NM_006231.4:c.-11C>T is a non-coding variant absent from these tables. Under generic ACMG/AMP fallback, SpliceAI predicts no splice impact (max delta 0.00), and REVEL/BayesDel do not score non-coding variants. No multiple lines of computational evidence support a deleterious effect.	spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
PP4	Not met	No phenotype specificity data are available. No evidence that NM_006231.4:c.-11C>T is enriched in patients with a specific POLE-associated phenotype compared to controls.
PP5	Not met	No reputable source (ClinVar, expert panel, published report) has classified NM_006231.4:c.-11C>T as pathogenic. The variant is absent from ClinVar and all reviewed publications.	clinvar
BA1	Not met	gnomAD v4.1 allele frequency is 0.00020% (grpmax FAF 9.95e-06), well below the 1% BA1 threshold. The variant is too rare to be considered a common benign polymorphism.	gnomad_v4
BS1	Not met	gnomAD v4.1 allele frequency is 0.00020%, below the 0.3% BS1 threshold. The variant is not observed at a frequency greater than expected for the disorder.	gnomad_v4
BS2	Not met	No data on observation of NM_006231.4:c.-11C>T in healthy adults for a fully penetrant early-onset disorder. The three gnomAD v4.1 alleles are from a general population cohort without phenotype annotation sufficient for BS2 determination.
BS3	Not met	No well-established functional studies demonstrate no deleterious effect of NM_006231.4:c.-11C>T. No in vitro or in vivo assays have characterized this promoter variant.
BS4	Not met	No segregation data are available to assess lack of segregation with disease for NM_006231.4:c.-11C>T.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. NM_006231.4:c.-11C>T is a non-coding promoter variant. Even though POLE truncating variants may be a disease mechanism, BP1 requires a missense variant to trigger.
BP2	Not met	No evidence that NM_006231.4:c.-11C>T has been observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant regardless of inheritance pattern.
BP3	N/A	Skipped per instructions.
BP4	Not met	The León-Castillo 2020 custom BP4 rule applies only to missense variants in Supplementary Tables S2/S3 with REVEL class 'likely benign' and ≥4 benign in silico results. NM_006231.4:c.-11C>T is a non-coding variant absent from these tables. Under generic ACMG/AMP fallback, SpliceAI predicts no splice impact (max delta 0.00), but this represents a single line of computational evidence and does not meet the 'multiple lines' requirement of generic BP4. REVEL/BayesDel are not applicable to non-coding variants.	spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
BP5	Not met	No evidence that NM_006231.4:c.-11C>T has been observed in a case with an alternative molecular cause for disease.
BP6	N/A	BP6 applies to synonymous (silent) variants for which a reputable source classifies the variant as benign. NM_006231.4:c.-11C>T is a non-coding promoter variant, not a synonymous coding variant. Even if extended by analogy, no reputable source has classified this variant as benign.
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006231.4:c.-11C>T is a non-coding 5'UTR/promoter variant, not a synonymous coding variant. While SpliceAI predicts no splice impact (max delta 0.00), the criterion is strictly defined for synonymous coding variants.

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