NM_006231.4:c.2044G>A

POLE · NP_006222.2:p.(Glu682Lys) · NM_006231.4

GRCh37: chr12:133245071 C>T · GRCh38: chr12:132668485 C>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2_Moderate

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Glu682Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The POLE c.2044G>A (p.Glu682Lys; p.E682K) variant has not been identified in the León-Castillo recurrent COSMIC/TCGA endometrial carcinoma POLE variant table and has been reported in ClinVar as a variant of uncertain significance.

This variant is present at very low frequency in gnomAD, with AF 4.16e-06 in v2.1 (1/240232 alleles) and AF 1.87e-06 in v4.1 (3/1600942 alleles), which is below the project's PM2 threshold of 0.1% and below benign frequency thresholds.

This missense change is not one of the exact POLE hotspot or recurrent exonuclease-domain substitutions specified by the León-Castillo framework for PM1 or PS4.

Available computational evidence does not establish a POLE-specific deleterious or benign pattern for this exact variant because it was not identified in the León-Castillo supplementary computational tables, and SpliceAI predicts no significant splice impact (max delta score 0.04).

Final determination: With PM2 at Moderate strength as the only met criterion, the variant does not satisfy the framework-defined combinations 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 variant is a missense change, NM_006231.4:c.2044G>A (p.Glu682Lys), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants; therefore PVS1 is not applicable.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that this nucleotide change creates the same amino acid substitution as a previously established pathogenic POLE variant, so PS1 was not assessed.
PS2	Not assessed	No confirmed de novo data were identified for this variant, so PS2 was not assessed.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect of p.Glu682Lys were identified, so PS3 was not assessed.
PS4	Not met	The León-Castillo POLE framework applies PS4 only to exact missense variants that recur in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count of at least 10 and belong to the established pathogenic set. p.Glu682Lys is not listed in that recurrence table, so PS4 is not met.	final_classification_framework vcep_path_250_323 vcep_path_250_323_s002
PM1	Not met	The León-Castillo POLE framework does not award PM1 for all exonuclease-domain variants and instead restricts PM1 to specific exact hotspot or recurrent pathogenic substitutions. p.Glu682Lys is not one of the exact substitutions specified for PM1_Strong, PM1_Moderate, or PM1_Supporting, so PM1 is not met.	final_classification_framework vcep_path_250_323 vcep_path_250_323_s002
PM2	Met	This variant is present at very low frequency in population databases and remains below the project's PM2 threshold of 0.1%: gnomAD v2.1 total AF is 4.16e-06 (1/240232 alleles; 0 homozygotes) and gnomAD v4.1 total AF is 1.87e-06 (3/1600942 alleles; 0 homozygotes). These values support PM2.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease setting, so PM3 was not assessed.
PM4	N/A	This variant is a missense substitution and does not cause a protein length change, so PM4 is not applicable.
PM5	Not assessed	No evidence was identified showing a different pathogenic missense change at codon 682 that would support PM5, so PM5 was not assessed.
PM6	Not assessed	No assumed de novo data were identified for this variant, so PM6 was not assessed.
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.
PP2	Not assessed	No retrieved gene-level evidence established that POLE is a gene in which missense variation is a common pathogenic mechanism in a way that supports PP2 for this specific variant, so PP2 was not assessed.
PP3	Not assessed	The León-Castillo custom PP3 rule applies only when the exact missense variant is present in Supplementary Table S2 or S3 with a REVEL class of likely disease causing and no more than one benign in silico result. p.Glu682Lys was not identified in those supplementary tables, and SpliceAI predicts no significant splice impact (max delta score 0.04), so PP3 was not assessed.	final_classification_framework vcep_path_250_323_s003 vcep_path_250_323_s004 spliceai
PP4	Not assessed	No phenotype information was provided that was sufficiently specific for a POLE-related disorder, so PP4 was not assessed.
PP5	Not assessed	ClinVar reports this variant as uncertain significance with criteria provided from a single submitter setting rather than as a concordant pathogenic classification from an expert source, so PP5 was not applied.	clinvar
BA1	Not met	This variant does not meet the BA1 population threshold. The highest observed population frequency is 5.52e-05 in gnomAD v2.1 East Asian alleles (0.00552%), which is well below the BA1 threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant does not meet the BS1 population threshold. The highest observed population frequency is 5.52e-05 in gnomAD v2.1 East Asian alleles (0.00552%), which is below the BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	Available population data do not show enough unaffected observations to support BS2, and no homozygotes were observed in gnomAD, so BS2 was not assessed.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies showing no damaging effect of p.Glu682Lys were identified, so BS3 was not assessed.
BS4	Not assessed	No segregation studies showing lack of cosegregation with disease were identified, so BS4 was not assessed.
BP1	Not assessed	No retrieved gene-specific evidence supported using BP1 for POLE, and this missense variant cannot be considered benign solely on variant class, so BP1 was not assessed.
BP2	Not assessed	No phase information or co-occurrence data were identified to support BP2, so BP2 was not assessed.
BP3	N/A	This variant is a missense substitution rather than an in-frame insertion or deletion in a repetitive region, so BP3 is not applicable.
BP4	Not assessed	The León-Castillo custom BP4 rule applies only when the exact missense variant is present in Supplementary Table S2 or S3 with a likely benign REVEL class and at least four benign in silico results. p.Glu682Lys was not identified in those tables, and SpliceAI predicts no significant splice impact (max delta score 0.04), which alone is not sufficient to apply BP4 for a missense variant, so BP4 was not assessed.	final_classification_framework vcep_path_250_323_s003 vcep_path_250_323_s004 spliceai
BP5	Not assessed	No case-level evidence was identified showing an alternate molecular explanation for the observed phenotype, so BP5 was not assessed.
BP6	Not assessed	ClinVar does not provide a reputable benign or likely benign classification for this variant; the current ClinVar assertion is uncertain significance, so BP6 was not applied.	clinvar
BP7	N/A	This variant is a missense substitution rather than a synonymous or deep intronic change, so BP7 is not applicable.

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