Variant classification summary

NM_006231.4:c.5811+16T>C

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133212462 A>G · GRCh38: chr12:132635876 A>G

Gene: POLE Transcript: NM_006231.4

Final call

Benign

BA1 stand-alone benign BS2 supporting benign BP4 supporting benign

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.?

gnomAD AF

0.0007456222039167353 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_006231.4:c.5811+16T>C is an intronic substitution in POLE at position +16 of intron 42. SpliceAI predicts no significant splice impact (max delta = 0.01).

2

This variant is present in gnomAD at an allele frequency of 1.41% in the African/African American subpopulation in v2.1 (350/24,822 alleles, including 4 homozygotes) and 1.42% in v4.1 (1,056/74,594 alleles, including 8 homozygotes). The gnomAD v2.1 grpmax filtering allele frequency is 1.27%. All exceed the >1% BA1 threshold.

3

This variant is observed in a homozygous state in gnomAD (4 individuals in v2.1, 8 in v4.1), consistent with a benign interpretation for a gene associated with rare Mendelian disease (BS2).

4

Seven clinical laboratories in ClinVar classify this variant as Likely benign (4) or Benign (3). While the review status is single submitter and does not meet the 3-star expert panel threshold for PP5/BP6, the unanimous direction of clinical classifications is consistent with a benign interpretation.

5

BA1 as a stand-alone benign criterion is sufficient to classify this variant as Benign per ACMG/AMP 2015 combination rules.

Final determination: BA1 alone (stand-alone benign) is sufficient to classify the variant as Benign per ACMG/AMP 2015 combination rules as preserved in both the León-Castillo 2020 custom POLE framework and the generic ACMG/AMP fallback.

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	This variant (NM_006231.4:c.5811+16T>C) is an intronic substitution at position +16 of intron 42, not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). The PVS1 generic framework does not apply.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	PS1 applies when a different pathogenic missense change at the same amino acid residue exists. This is an intronic variant with no amino acid change.
PS2	Not met	No de novo data are available for this variant.
PS3	N/A	This is a deep intronic substitution (c.5811+16T>C) with no predicted protein consequence. No functional studies address this variant and no systematic functional characterization of this intronic region is available.
PS4	N/A	The custom León-Castillo 2020 PS4 rule applies only to specific recurrent POLE missense hotspot variants in endometrial carcinoma cohorts. This intronic variant is not a missense change and is absent from the supplementary recurrence tables.	vcep_path_250_323_s002
PS5	N/A	PS5 requires an established pathogenic variant at the same amino acid residue. This is an intronic variant with no amino acid change.
PM1	N/A	The León-Castillo 2020 custom PM1 framework applies only to specific POLE missense variants within the exonuclease domain. This is an intronic variant and is not eligible.	vcep_path_250_323
PM2	Not met	This variant is present in gnomAD v2.1 at an overall allele frequency of 0.134% (370/275,742 alleles), exceeding the 0.1% PM2 threshold. It is not absent from the general population.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue. This is an intronic variant with no amino acid residue; PM5 candidate harvesting confirms not applicable.	pm5_candidates
PM6	Not met	No de novo data are available for this variant.
PP1	Not met	No segregation data are available for this variant.
PP2	N/A	PP2 applies to missense variants in genes where missense variants are a common disease mechanism. This is an intronic substitution.
PP3	Not met	SpliceAI predicts no significant splice impact (max delta = 0.01). The León-Castillo 2020 custom PP3 rule applies only to missense variants in Supplementary Tables S2/S3. No in silico tool (REVEL, BayesDel, HCI prior) returns a score for this 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 assessed	No phenotype specificity data are available to assess whether this variant's phenotype is specific for the gene/disease.
PP5	Not met	ClinVar classifies this variant as Likely benign (4 laboratories) and Benign (3 laboratories) with review status 'criteria provided, single submitter.' This does not meet the 3-star expert panel threshold required for PP5 application. Seven clinical laboratories independently classify this as benign or likely benign, which is consistent with a benign interpretation.	clinvar
BA1	Met	This variant has an allele frequency of 1.41% in the African/African American subpopulation in gnomAD v2.1 (350/24,822 alleles, 4 homozygotes) and 1.42% in gnomAD v4.1 (1,056/74,594 alleles, 8 homozygotes). The gnomAD v2.1 grpmax filtering allele frequency is 1.27% (95% CI upper bound). All exceed the project threshold of >1% for BA1, indicating this variant is too common to be a pathogenic cause of a rare Mendelian disorder.	gnomad_v2 gnomad_v4
BS1	Not met	The overall allele frequency in gnomAD v2.1 is 0.134% (370/275,742 alleles), which is below the 0.3% BS1 threshold. The variant is not sufficiently common at the overall population level to meet BS1, though it is concentrated in the African/African American subpopulation.	gnomad_v2
BS2	Met	This variant is observed in a homozygous state in 4 individuals in gnomAD v2.1 and 8 individuals in gnomAD v4.1, indicating it is present in healthy adults without apparent disease. Observation in homozygotes supports a benign interpretation for a rare disease gene.	gnomad_v2 gnomad_v4
BS3	N/A	This is an intronic variant with SpliceAI predicting no splice impact (delta 0.01). No functional studies that demonstrate no deleterious effect exist for this variant.	spliceai
BS4	Not met	No segregation data are available to demonstrate lack of segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is an intronic substitution.
BP2	Not met	No data are available regarding observation in trans with a pathogenic variant.
BP4	Met	SpliceAI predicts no significant splice impact for this intronic variant (max delta = 0.01). Multiple in silico tools (REVEL, BayesDel) cannot be applied to an intronic variant. For a deep intronic substitution at position +16, the absence of a predicted splicing alteration constitutes computational evidence suggesting no impact on the gene product.	spliceai
BP5	Not met	No data available regarding an alternate molecular basis for disease in affected individuals harboring this variant.
BP6	Not met	ClinVar classifies this variant as Likely benign (4 laboratories) and Benign (3 laboratories) with review status 'criteria provided, single submitter.' This does not meet the 3-star expert panel threshold required for BP6 application. Seven clinical laboratories independently support a benign or likely benign classification.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants where splicing prediction algorithms predict no impact. This is an intronic substitution (c.5811+16T>C), not a synonymous coding variant, and does not fit the BP7 criterion definition.	PMID:25741868

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