NM_006231.4:c.1718G>A

POLE · NP_006222.2:p.(Arg573Gln) · NM_006231.4

GRCh37: chr12:133248877 C>T · GRCh38: chr12:132672291 C>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Arg573Gln)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The POLE c.1718G>A (p.Arg573Gln) variant has not been observed in COSMIC somatic cancer records and has been reported in ClinVar as uncertain significance by 3 clinical laboratories.

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a very low overall allele frequency of 1.85855e-06 (0.00019%, 3/1614158 alleles), with the highest observed population frequency 0.000165017 (0.01650%, 1/6060 alleles), which remains below the 0.1% PM2 rarity threshold.

p.Arg573Gln is not listed among the recurrent POLE exonuclease-domain variants in León-Castillo et al. Supplementary Table S1 and was not identified in the Cancer Hotspots review, which does not support PM1 or the POLE-specific PS4 recurrence rule.

Available computational evidence does not support a protein-damaging or benign in silico assignment because this exact variant is not listed in the POLE supplementary in silico tables, REVEL is 0.228, and SpliceAI shows a possible splice impact with a max delta score of 0.20.

Final determination: PM2 alone does 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 is a missense variant, and the generic PVS1 framework applies to nonsense, frameshift, or canonical ±1,2 splice variants rather than to p.(Arg573Gln). Available evidence does not support a loss-of-function PVS1 mechanism for this specific change.	output/pvs1_variant_assessment.json output/pvs1_gene_context.json
PS1	Not assessed	No evidence was identified showing that a different nucleotide change causes the same p.Arg573Gln amino acid substitution and has already been established as pathogenic or likely pathogenic, so PS1 cannot be assessed from the available data.	output/case_summary.json output/evidence.json
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified, so PS2 cannot be applied.	output/literature_pass.json
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect of p.Arg573Gln were identified, so PS3 cannot be applied.	output/literature_pass.json output/evidence.json
PS4	Not met	The local POLE framework applies PS4 only to exact recurrent exonuclease-domain variants that are present in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count of at least 10 and that belong to the established pathogenic set. p.Arg573Gln was not found in COSMIC and was not listed in Supplementary Table S1, so this criterion is not met.	output/final_classification_framework.json output/evidence.json vcep_db/POLE/files/PATH-250-323-s002.xlsx
PM1	Not met	The local POLE framework restricts PM1 to specific exact exonuclease-domain hotspot or recurrent pathogenic substitutions from León-Castillo et al. 2020. p.Arg573Gln is not one of the exact PM1-listed substitutions and was not identified in Supplementary Table S1 or Cancer Hotspots, so PM1 is not met.	output/final_classification_framework.json output/evidence.json vcep_db/POLE/files/PATH-250-323-s002.xlsx
PM2	Met	This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a very low overall allele frequency of 1.85855e-06 (0.00019%, 3/1614158 alleles), with the highest observed population frequency 0.000165017 (0.01650%, 1/6060 alleles) in Middle Eastern individuals. These values are below the project's default PM2 rarity threshold of 0.1%, supporting PM2.	output/evidence.json output/case_summary.json
PM3	Not assessed	No evidence was identified showing this variant in trans with another pathogenic variant in a recessive disorder context, so PM3 cannot be assessed.	output/literature_pass.json
PM4	N/A	PM4 applies to protein length changes such as in-frame insertions, in-frame deletions, or stop-loss variants. This is a missense substitution and does not alter protein length.	output/case_summary.json
PM5	Not assessed	No pathogenic or likely pathogenic missense comparison variant at the same amino acid residue was identified in the available evidence, so PM5 cannot be assessed.	output/case_summary.json output/evidence.json
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified, so PM6 cannot be applied.	output/literature_pass.json
PP1	Not assessed	No segregation data were identified to show that this variant tracks with disease in affected family members, so PP1 cannot be assessed.	output/literature_pass.json
PP2	Not assessed	No gene-specific evidence was retrieved to show that pathogenic POLE variation is predominantly missense with a low rate of benign missense variation, so PP2 cannot be assessed from the available data.	output/final_classification_framework.json
PP3	Not met	The local POLE framework applies PP3 only when the exact 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.Arg573Gln was not listed in those supplementary tables. In the generic computational review, REVEL is 0.228 and SpliceAI shows only a borderline signal at 0.20, so available in silico evidence does not support a deleterious PP3 assignment.	output/final_classification_framework.json output/evidence.json output/case_summary.json vcep_db/POLE/files/PATH-250-323-s003.xlsx vcep_db/POLE/files/PATH-250-323-s004.xlsx
PP4	Not assessed	No phenotype or family history data specific enough to establish a highly specific POLE-related clinical presentation were identified, so PP4 cannot be assessed.	output/case_summary.json
PP5	N/A	ClinVar reports this variant as uncertain significance, and assertion-only criteria are not applied as independent evidence in this review. PP5 is therefore not applicable.	output/evidence.json output/case_summary.json
BA1	Not met	The highest observed population frequency is 0.000165017 (0.01650%, 1/6060 alleles), which is below the project's BA1 threshold of 1%. This variant therefore does not meet BA1.	output/evidence.json output/case_summary.json
BS1	Not met	The highest observed population frequency is 0.000165017 (0.01650%, 1/6060 alleles), which is below the project's BS1 threshold of 0.3%. This variant therefore does not meet BS1.	output/evidence.json output/case_summary.json
BS2	Not assessed	No evidence was identified showing this variant in healthy adults in a manner sufficient to support BS2, so the criterion cannot be assessed.	output/evidence.json
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect of p.Arg573Gln were identified, so BS3 cannot be applied.	output/literature_pass.json
BS4	Not assessed	No segregation evidence showing lack of cosegregation with disease was identified, so BS4 cannot be assessed.	output/literature_pass.json
BP1	Not assessed	No gene-specific evidence was retrieved showing that POLE disease is primarily caused by truncating variants with missense variants rarely pathogenic, so BP1 cannot be assessed.	output/pvs1_gene_context.json output/final_classification_framework.json
BP2	Not assessed	No phase data or co-occurrence evidence with another pathogenic variant were identified, so BP2 cannot be assessed.	output/literature_pass.json
BP3	N/A	BP3 applies to in-frame insertions or deletions in repetitive regions without known function. This is a missense substitution, so BP3 is not applicable.	output/case_summary.json
BP4	Not met	The local POLE framework applies BP4 only when the exact variant is present in Supplementary Table S2 or S3 with a REVEL class of likely benign and at least four benign in silico results. p.Arg573Gln was not listed in those tables. In the generic computational review, REVEL is low at 0.228, but SpliceAI shows a possible splice impact with a max delta score of 0.20 rather than clearly no splice effect, so BP4 is not met.	output/final_classification_framework.json output/evidence.json output/case_summary.json vcep_db/POLE/files/PATH-250-323-s003.xlsx vcep_db/POLE/files/PATH-250-323-s004.xlsx
BP5	Not assessed	No evidence was identified showing an alternate molecular cause that fully explains the phenotype, so BP5 cannot be assessed.	output/case_summary.json
BP6	N/A	ClinVar does not provide a benign or likely benign expert assertion for this variant, and assertion-only criteria are not applied as independent evidence. BP6 is therefore not applicable.	output/evidence.json output/case_summary.json
BP7	N/A	BP7 applies to synonymous or certain intronic variants without predicted splice impact. This is a missense variant, so BP7 is not applicable.	output/case_summary.json output/evidence.json

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.