NM_006231.4:c.2172G>A

POLE · NP_006222.2:p.(Ala724=) · NM_006231.4

GRCh37: chr12:133244943 C>T · GRCh38: chr12:132668357 C>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Ala724=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The POLE c.2172G>A (p.Ala724=) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar predominantly as likely benign, with five likely benign submissions and one submission of uncertain significance.

This variant is present at low frequency in gnomAD, with total allele frequencies of 0.00400% in v2.1 and 0.00166% in v4.1, both below the project's PM2 threshold of 0.1% and below the BS1 threshold of 0.3%.

This is a synonymous change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01; it is also not among the missense hotspot or computationally selected variants used for the custom POLE PM1, PS4, PP3, and BP4 rules.

Final determination: PM2 at moderate strength and BP7 at supporting benign strength do not satisfy the combination thresholds for Pathogenic, Likely Pathogenic, Likely Benign, or Benign; therefore this 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 variant is a synonymous change, p.(Ala724=), and does not fall in the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1 or 2 splice-site variants. Available evidence does not support use of PVS1 for this variant.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 is intended for a different nucleotide change producing the same amino acid change as an established pathogenic variant. This variant is synonymous and no qualifying PS1 evidence was identified.	clinvar
PS2	Not assessed	No confirmed de novo data with parental testing were identified, so PS2 could not be assessed.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 could not be assessed.
PS4	Not met	This variant has not been reported in COSMIC, and it is not one of the exact recurrent pathogenic missense variants eligible for the custom POLE PS4 rule. Available evidence does not show increased prevalence in affected individuals sufficient to support PS4.	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
PM1	Not met	This is a synonymous variant, p.(Ala724=), and it is not one of the exact POLE missense hotspot or recurrent exonuclease-domain variants specified in the custom POLE PM1 framework. Available evidence does not support PM1.	hotspots 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
PM2	Met	Population frequency is below the project's PM2 threshold of 0.1% in both gnomAD v2.1 and gnomAD v4.1. The observed total allele frequency is 0.00400% in v2.1 (10/249782 alleles) and 0.00166% in v4.1 (26/1568268 alleles), which is below the 0.1% threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	No data on allelic phase with another pathogenic variant were identified, so PM3 could not be assessed.
PM4	N/A	PM4 applies to protein length changes caused by in-frame insertions, deletions, or stop-loss variants. This variant is synonymous and does not alter protein length.
PM5	N/A	PM5 applies to a novel missense change at an amino-acid residue where a different missense change is established as pathogenic. This variant is synonymous and does not create a missense substitution.
PM6	Not assessed	No assumed de novo data without confirmed parentage were identified, so PM6 could not be assessed.
PP1	Not assessed	No segregation data were identified, so PP1 could not be assessed.
PP2	N/A	PP2 is a missense-based criterion and is not applicable to this synonymous variant.
PP3	Not met	This synonymous variant is not eligible for the custom POLE PP3 rule, which is restricted to exact missense variants listed in the León-Castillo supplementary computational tables. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, so available computational evidence does not support PP3.	spliceai vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_3 vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4
PP4	Not assessed	No phenotype or family history data sufficiently specific for POLE-related disease were identified, so PP4 could not be assessed.
PP5	N/A	PP5 was not applied because external assertions alone were not used as primary evidence for this interpretation.	clinvar
BA1	Not met	Population frequency does not reach the BA1 threshold of 1%. The observed total allele frequency is 0.00400% in gnomAD v2.1 and 0.00166% in gnomAD v4.1, which is below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not exceed the BS1 threshold of 0.3%. The highest observed population frequency is 0.03269% in gnomAD v2.1 African/African American and 0.02041% in gnomAD v4.1 African/African American, both below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	Although this variant is present in population databases, no disease-specific evidence was identified to show observation in unaffected individuals is sufficient to support BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect of this specific variant were identified, so BS3 could not be assessed.
BS4	Not assessed	No evidence showing lack of segregation with disease in affected family members was identified, so BS4 could not be assessed.
BP1	N/A	BP1 is a missense-based criterion and is not applicable to this synonymous variant.
BP2	Not assessed	No phase data or observations with another variant were identified, so BP2 could not be assessed.
BP3	N/A	BP3 applies to in-frame indels in repetitive regions without known function. This variant is a synonymous substitution and BP3 is not applicable.
BP4	N/A	The custom POLE BP4 rule is restricted to exact missense variants represented in the León-Castillo supplementary computational tables. This variant is synonymous, so BP4 was not applied.	vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_3 vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4
BP5	Not assessed	No alternate molecular explanation for the phenotype was provided, so BP5 could not be assessed.
BP6	N/A	BP6 was not applied because external classifications alone were not used as stand-alone benign evidence.	clinvar
BP7	Met	This is a synonymous variant, p.(Ala724=), with no amino-acid change. It is not a canonical splice consensus variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which supports BP7.	spliceai pvs1_variant_assessment

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.