NM_006231.4:c.1367C>T

POLE · NP_006222.2:p.(Ala456Val) · NM_006231.4

GRCh37: chr12:133249856 G>A · GRCh38: chr12:132673270 G>A

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2_Supporting PP3_Supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Ala456Val)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The POLE c.1367C>T (p.Ala456Val) variant has been observed in somatic cancers in COSMIC (COSV57673561, n=2) and has not been reported in ClinVar.

The variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed population frequency of 0 that is below the project's PM2 threshold of 0.1%.

In León-Castillo Supplementary Table S3, p.Ala456Val is listed as likely disease causing with 0 benign in silico results, meeting the local POLE PP3 rule; SpliceAI predicts no significant splice impact with a maximum delta score of 0.10.

Final determination: PM2_Supporting and PP3_Supporting do not meet the framework thresholds for Likely Pathogenic, Likely Benign, Benign, or Pathogenic; therefore the variant is classified as 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 missense variant does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice-site variants, so PVS1 is not applicable.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No established pathogenic variant causing the same amino acid change p.(Ala456Val) was identified, so PS1 is not met.	clinvar
PS2	Not assessed	No confirmed de novo data with verified maternity and paternity were identified, so PS2 was not assessed.
PS3	Not assessed	No validated variant-specific functional study demonstrating a damaging effect for p.(Ala456Val) was identified in the available evidence, so PS3 was not assessed.	PMID:23528559 PMID:26763250 PMID:29056344 PMID:31624068
PS4	Not met	This variant has been reported in COSMIC 2 times, but the local POLE framework requires recurrence in both the COSMIC and TCGA endometrial carcinoma cohorts, a combined endometrial carcinoma count of at least 10, and membership in the established pathogenic set; these requirements are not met for p.(Ala456Val).	cosmic vcep_p_a_t_h___2_5_0___3_2_3 vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_2 final_classification_framework
PM1	Not met	The local POLE framework does not allow PM1 based only on location in the exonuclease domain. p.(Ala456Val) is not one of the exact hotspot or recurrent substitutions specified for PM1, and the same codon shows heterogeneous substitutions including the hotspot p.(Ala456Pro), so PM1 is not met.	vcep_p_a_t_h___2_5_0___3_2_3 vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_2 vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4 final_classification_framework
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the project's PM2 threshold of 0.1%.	gnomad_v2 gnomad_v4
PM3	Not assessed	No trans data with another pathogenic variant in a recessive disorder context were identified, so PM3 was not assessed.
PM4	N/A	This is a missense substitution and not a protein length-changing variant, so PM4 is not applicable.	case_summary_json
PM5	Not met	A different substitution at the same codon, p.(Ala456Pro), is included in the local POLE hotspot set, but the same residue also shows other non-equivalent substitutions in the supplementary tables, including p.A456G and p.A456V. Because the local framework warns against extrapolating codon-level pathogenicity across substitutions, PM5 is not met.	vcep_p_a_t_h___2_5_0___3_2_3 vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_2 vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4 final_classification_framework
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified, so PM6 was not assessed.
PP1	Not assessed	No segregation data were identified, so PP1 was not assessed.
PP2	Not assessed	Gene-level evidence required to determine whether missense variation is a common disease mechanism and benign missense variation is low was not identified, so PP2 was not assessed.
PP3	Met	This variant is listed in León-Castillo Supplementary Table S3 as p.A456V with REVEL classified as likely disease causing and 0 benign in silico results, which meets the local POLE PP3 rule. SpliceAI also predicts no significant splice impact with a maximum delta score of 0.10, supporting interpretation as a missense effect rather than a splice-disrupting variant.	vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4 spliceai
PP4	Not assessed	No phenotype data sufficiently specific for a single genetic etiology were identified, so PP4 was not assessed.
PP5	Not assessed	No reputable source classification for this exact variant was identified, so PP5 was not assessed.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the benign stand-alone threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the benign strong threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence showing this variant in healthy adult individuals at a frequency inconsistent with disease penetrance was identified, so BS2 was not assessed.
BS3	Not assessed	No validated variant-specific functional study demonstrating no damaging effect for p.(Ala456Val) was identified, so BS3 was not assessed.	PMID:23528559 PMID:26763250 PMID:29056344 PMID:31624068
BS4	Not assessed	No segregation data showing lack of cosegregation with disease were identified, so BS4 was not assessed.
BP1	N/A	BP1 is not applicable because POLE does not fit a disease model in which only truncating variants are expected to be pathogenic; the local POLE framework specifically addresses pathogenic missense variants.	final_classification_framework pvs1_gene_context
BP2	Not assessed	No phase data showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant were identified, so BP2 was not assessed.
BP3	N/A	This is not an in-frame deletion or insertion in a repetitive region, so BP3 is not applicable.	case_summary_json
BP4	Not met	The local POLE BP4 rule is not met because León-Castillo Supplementary Table S3 lists p.A456V as likely disease causing, not likely benign, and the benign in silico result count is 0 rather than at least 4.	vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4
BP5	Not assessed	No alternate molecular explanation fully accounting for the phenotype was identified, so BP5 was not assessed.
BP6	Not assessed	No reputable source classified this exact variant as benign or likely benign, so BP6 was not assessed.	clinvar
BP7	N/A	This is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable.	case_summary_json 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.