NM_006231.4:c.1360-6C>T

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133249869 G>A · GRCh38: chr12:132673283 G>A

Gene: POLE Transcript: NM_006231.4

Final call

Likely Benign

BS1 supporting benign BS2 supporting benign

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.?

gnomAD AF

0.00023873955673175707 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_006231.4:c.1360-6C>T is present in gnomAD v4.1 at an allele frequency of 0.0239% overall (376/1,574,938 alleles) and 0.353% in the African/African American subpopulation (262/74,194 alleles), exceeding the 0.3% threshold for BS1 at supporting benign strength.

Three homozygous individuals for c.1360-6C>T are observed in gnomAD v4.1 (2 African/African American, 1 South Asian), which is inconsistent with a pathogenic role in an autosomal dominant cancer predisposition syndrome, satisfying BS2 at supporting benign strength.

SpliceAI predicts no significant splice impact for this intronic variant (max delta score = 0.15, below the 0.2 threshold). The variant does not disrupt the canonical splice consensus sequence.

This variant has been reported in ClinVar as Likely benign by 8 clinical laboratories and Benign by 5 clinical laboratories (ClinVar ID 240389), with concordance across 13 clinical submitters, consistent with a benign interpretation.

No pathogenic ACMG/AMP criteria are met. Two supporting benign criteria (BS1 and BS2) are met, satisfying the >=2 supporting benign rule for a Likely Benign classification per the ACMG/AMP 2015 framework with custom POLE specifications.

Final determination: Two supporting benign criteria (BS1 and BS2) satisfy the '>=2 Supporting benign' rule for a Likely Benign classification per the custom POLE framework.

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.1360-6C>T is an intronic splice region variant located 6 bases upstream of exon 13. It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. SpliceAI predicts no significant splice impact (max delta score = 0.15). PVS1 is not applicable.	pvs1_variant_assessment pvs1_gene_context spliceai
PS1	N/A	PS1 applies only to nucleotide changes producing the same amino acid change as an established pathogenic missense variant. This is an intronic variant with no amino acid change.
PS2	Not met	No de novo observation of NM_006231.4:c.1360-6C>T with confirmed maternity and paternity has been reported in the available literature or ClinVar submissions.
PS3	Not met	No variant-specific functional data exists for NM_006231.4:c.1360-6C>T. The Leon-Castillo et al. 2020 VCEP supplementary tables contain only missense variants in the exonuclease domain; this intronic variant is not represented. No experimental studies characterizing this splice region variant were identified.	vcep_path_250_323
PS4	Not met	The custom POLE PS4 framework rule requires exact missense variant recurrence in both COSMIC and TCGA endometrial carcinoma cohorts with combined count >=10 and belonging to the established pathogenic set. This is an intronic variant, not present in COSMIC and not listed in the VCEP recurrence tables. No case-control or prevalence data is available for germline assessment.	vcep_path_250_323_s002
PS5	N/A	PS5 applies only to novel missense changes at the same amino acid position as a known pathogenic missense change. This is an intronic variant with no amino acid change.
PM1	Not met	The custom POLE PM1 framework rules apply only to specific missense variants in the exonuclease domain (hotspot and non-hotspot tiers defined by Leon-Castillo et al. 2020). This intronic variant (c.1360-6C>T) is not a missense change and is not among the enumerated exonuclease domain substitutions. No hotspot or critical functional domain evidence applies to this intronic position.	vcep_path_250_323_s002
PM2	Not met	NM_006231.4:c.1360-6C>T is present in gnomAD at appreciable frequency: v2.1 AF = 0.0357% (101/282,736 alleles), v4.1 AF = 0.0239% (376/1,574,938 alleles). The African/African American subpopulation AF exceeds the 0.3% BS1 threshold (v2.1: 0.324%; v4.1: 0.353%). Three homozygotes are observed in gnomAD v4.1. The variant is not absent from population controls, and the subpopulation frequency and homozygote count are inconsistent with PM2 application.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a missense change at the same amino acid residue as a known pathogenic missense change. c.1360-6C>T is an intronic variant with no protein consequence (NP_006222.2:p.?), so same-residue missense comparator semantics cannot be applied.	pm5_candidates
PM6	Not met	No de novo observation of NM_006231.4:c.1360-6C>T with confirmed maternity and paternity has been reported. PM6 requires a de novo event in a patient with the disease and no family history.
PP1	Not met	No co-segregation data is available for NM_006231.4:c.1360-6C>T. PP1 requires evidence of segregation with disease in multiple affected family members.
PP2	Not met	PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense variants are a common mechanism of disease. c.1360-6C>T is an intronic variant, not a missense change. PP2 does not apply.
PP3	Not met	The custom POLE PP3 framework rule requires the exact missense variant to appear in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and <=1 benign in silico result. This intronic variant is not present in those tables. Generic PP3 assessment: SpliceAI max delta score is 0.15, below the 0.2 threshold for predicted splice impact. REVEL and BayesDel scores are unavailable (intronic variant). Multiple lines of computational evidence do not support a deleterious effect.	spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
PP4	Not met	No specific patient phenotype data is available for individuals harboring NM_006231.4:c.1360-6C>T. PP4 requires the variant to be identified in a patient with a phenotype highly specific for the gene/disease.
PP5	Not met	ClinVar reports NM_006231.4:c.1360-6C>T as Likely benign (8 clinical laboratories) and Benign (5 clinical laboratories), not as pathogenic. The ClinVar review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold for PP5 application. No reputable source has reported this variant as pathogenic.	clinvar
BA1	Not met	The highest subpopulation allele frequency for NM_006231.4:c.1360-6C>T is 0.353% (African/African American in gnomAD v4.1), which is below the 1% BA1 threshold for non-VCEP assessment.	gnomad_v2 gnomad_v4
BS1	Met	The allele frequency of NM_006231.4:c.1360-6C>T in the African/African American subpopulation exceeds the 0.3% BS1 threshold for non-VCEP assessment: 0.324% in gnomAD v2.1 (81/24,970 alleles) and 0.353% in gnomAD v4.1 (262/74,194 alleles, including 2 homozygotes). The gnomAD v4.1 grpmax FAF is 0.318% (>0.3%). This frequency is greater than expected for a pathogenic variant in a rare cancer predisposition gene.	gnomad_v2 gnomad_v4
BS2	Met	Three homozygous individuals for NM_006231.4:c.1360-6C>T are observed in gnomAD v4.1 (exome data: 2 in the African/African American subpopulation, 1 in the South Asian subpopulation). For a gene where pathogenic germline variants are associated with a rare autosomal dominant cancer predisposition syndrome (POLE-associated polyposis and colorectal cancer), the observation of homozygous individuals in a population database is inconsistent with a pathogenic role.	gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate that NM_006231.4:c.1360-6C>T has no damaging effect on protein function or splicing. The variant has not been characterized in any functional assay.
BS4	Not met	No co-segregation data is available to assess lack of segregation with disease. BS4 requires the variant to be observed in trans or to show lack of segregation in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. c.1360-6C>T is an intronic variant, not a missense change.
BP2	Not met	No observation of NM_006231.4:c.1360-6C>T in trans with a known pathogenic POLE variant has been reported. BP2 requires co-occurrence data with a pathogenic variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. c.1360-6C>T is a single nucleotide substitution in an intron, not an in-frame indel.
BP4	Not met	The custom POLE BP4 framework rule requires the exact missense variant to appear in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and >=4 benign in silico results. This intronic variant is not present in those tables. Generic BP4: SpliceAI max delta score is 0.15 (<0.2 threshold), suggesting no splice impact, but multiple independent lines of computational evidence are not available to meet BP4 requirements. REVEL and BayesDel are unavailable for this intronic variant.	spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
BP5	Not met	No evidence is available demonstrating that NM_006231.4:c.1360-6C>T is found in a case with an alternate molecular basis for disease. BP5 requires documentation of a different causative variant explaining the phenotype.
BP6	Not met	ClinVar reports NM_006231.4:c.1360-6C>T as Likely benign (8 clinical laboratories) and Benign (5 clinical laboratories). However, the review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold required for BP6 application under the project's PP5/BP6 rule. The automatic BP6 rule requires ClinVar 3-star expert panel status.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants where splicing prediction algorithms predict no impact on the splice consensus sequence and the nucleotide is not highly conserved. c.1360-6C>T is an intronic variant, not a synonymous coding change.

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