NM_006231.4:c.2137G>A

POLE · NP_006222.2:p.(Glu713Lys) · NM_006231.4

GRCh37: chr12:133244978 C>T · GRCh38: chr12:132668392 C>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2_Supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Glu713Lys)

gnomAD AF

3.108003108003108e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The POLE c.2137G>A (p.Glu713Lys; p.E713K) variant has not been identified as a recurrent somatic POLE hotspot in the endometrial carcinoma datasets summarized by León-Castillo et al. and has been reported in ClinVar as a variant of uncertain significance.

This variant is rare in population databases, with an allele frequency of 0.00081% (2/247784) in gnomAD v2.1 and 0.00031% (5/1608750) in gnomAD v4.1, and it is absent from gnomAD-Canada.

Computational evidence does not support a splice-disrupting effect, with a SpliceAI maximum delta score of 0.01, and the missense predictor scores are not strongly damaging (REVEL 0.246; BayesDel -0.033673).

Final determination: With only PM2_Supporting met, the variant does not satisfy the defined thresholds for likely pathogenic, pathogenic, likely benign, or benign classification and is therefore classified as a variant of 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	This is a missense variant, not a nonsense, frameshift, or canonical ±1/2 splice-site variant, so the generic PVS1 loss-of-function framework does not apply.	pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No evidence was identified that this nucleotide change produces the same amino acid change as an established pathogenic or likely pathogenic variant.	clinvar
PS2	Not assessed	No confirmed de novo data were identified.
PS3	Not assessed	No variant-specific functional study demonstrating a damaging effect was identified.	oncokb
PS4	Not met	Under the local POLE framework, PS4_Supporting requires the exact missense variant to be recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count of at least 10 and to belong to the established pathogenic set. This variant was not identified in the supplementary recurrence table and does not meet that rule.	final_classification_framework vcep_path_250_323_s002
PM1	Not met	Under the local POLE framework, PM1 is restricted to specific exonuclease-domain hotspot or recurrent substitutions from León-Castillo et al. This variant is not one of the listed qualifying substitutions and was not identified as a hotspot in the reviewed somatic hotspot resources.	final_classification_framework vcep_path_250_323_s002 hotspots
PM2	Met	This variant is rare in population databases. Its allele frequency is 0.00081% in gnomAD v2.1 (2/247784) and 0.00031% in gnomAD v4.1 (5/1608750), both below the 0.1% PM2 threshold, and it is absent from gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	No evidence was identified for this variant occurring in trans with a pathogenic variant in a recessive disease context.
PM4	N/A	This is a missense substitution and does not produce a protein length change.
PM5	N/A	Available review materials did not establish that classic same-residue PM5 logic can be safely applied for this POLE framework, and no validated same-residue comparator set was confirmed for this variant.	pm5_candidates final_classification_framework
PM6	Not assessed	No assumed de novo data were identified.
PP1	Not assessed	No segregation data were identified.
PP2	Not assessed	No gene-specific evidence set was identified to support applying PP2 to this missense variant.	final_classification_framework
PP3	Not met	Under the local POLE framework, PP3 requires the exact missense variant to appear in the reviewed supplementary in silico tables with a 'likely disease causing' REVEL class and no more than one benign in silico result. This variant was not identified in those tables. In the generic computational review, REVEL is 0.246, BayesDel is -0.033673, and SpliceAI max delta score is 0.01, which do not provide a strong damaging computational signal.	final_classification_framework vcep_path_250_323_s003 vcep_path_250_323_s004 revel bayesdel spliceai
PP4	Not assessed	No phenotype or tumor signature data specific enough to support PP4 were identified.
PP5	N/A	Assertion-only pathogenic evidence was not used. ClinVar contains only non-expert uncertain-significance submissions for this variant.	clinvar
BA1	Not met	The population frequency is far below the 1% BA1 threshold: 0.00081% in gnomAD v2.1 and 0.00031% in gnomAD v4.1.	gnomad_v2 gnomad_v4
BS1	Not met	The population frequency is below the 0.3% BS1 threshold: 0.00081% in gnomAD v2.1 and 0.00031% in gnomAD v4.1.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in well-phenotyped healthy individuals at a frequency sufficient for BS2.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	No variant-specific functional study demonstrating a normal or benign effect was identified.	oncokb
BS4	Not assessed	No non-segregation data were identified.
BP1	N/A	BP1 was not applied because there is no evidence here that missense variation is generally a less relevant mechanism for POLE-related disease than truncating variation.	final_classification_framework
BP2	Not assessed	No phase data with another variant were identified.
BP3	N/A	This is not an in-frame deletion or insertion in a repetitive region.
BP4	Not met	Under the local POLE framework, BP4 requires the exact missense variant to appear in the reviewed supplementary in silico tables with a benign-leaning REVEL class and at least four benign in silico results. This variant was not identified in those tables. In the generic computational review, SpliceAI predicts no significant splice impact (max delta 0.01), but REVEL 0.246 and BayesDel -0.033673 do not by themselves provide sufficiently validated benign missense evidence to apply BP4.	final_classification_framework vcep_path_250_323_s003 vcep_path_250_323_s004 spliceai revel bayesdel
BP5	Not assessed	No alternate molecular explanation data were identified for the observed condition.
BP6	N/A	Assertion-only benign evidence was not used, and no benign ClinVar submission was identified for this variant.	clinvar
BP7	N/A	BP7 does not apply because this is not a synonymous or intronic variant, although SpliceAI does not predict a significant splice effect.	spliceai

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.