NM_006231.4:c.5312C>T

POLE · NP_006222.2:p.(Thr1771Met) · NM_006231.4

GRCh37: chr12:133218299 G>A · GRCh38: chr12:132641713 G>A

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2_Moderate

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Thr1771Met)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The POLE c.5312C>T (p.Thr1771Met) variant has been observed in somatic cancers in COSMIC (COSV57679989, n=2) and has been reported in ClinVar as a variant of uncertain significance.

The variant is present at low frequency in population databases, with gnomAD v2.1 AF 3.9888e-05 (10/250702) and gnomAD v4.1 AF 4.09054e-05 (66/1613480), with no homozygotes reported; these values are below the PM2 threshold of 0.1% and below the BS1 and BA1 thresholds of 0.3% and 1%, respectively.

No validated variant-specific functional assay evidence was identified for p.(Thr1771Met).

SpliceAI predicts no significant splice impact (maximum delta score 0.04), and the local REVEL score is 0.178; however, the variant is not represented in the León-Castillo POLE supplementary computational tables, so the custom POLE PP3 and BP4 rules were not applied.

Final determination: PM2 at moderate strength alone does not meet the ACMG/AMP combination threshold for likely pathogenic, pathogenic, likely benign, or benign classification; therefore the variant is classified as 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	NM_006231.4:c.5312C>T predicts a missense change, p.(Thr1771Met), rather than a null variant, and the generic PVS1 assessment does not place this variant in a nonsense, frameshift, or canonical splice category, so PVS1 is not applicable.	pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No evidence was identified showing that a different nucleotide change causing the same amino acid substitution p.(Thr1771Met) is established as pathogenic or likely pathogenic.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified.
PS3	Not assessed	No validated variant-specific functional studies were identified showing a damaging effect for p.(Thr1771Met).	oncokb
PS4	Not met	Under the custom POLE framework, PS4 is restricted to exact variants recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with combined count at least 10 and belonging to the established pathogenic set. p.(Thr1771Met) is not included in that set, and COSMIC shows only 2 somatic observations, which is below the framework requirement.	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 custom POLE framework does not assign PM1 by domain location alone and limits PM1 to specific exact substitutions from León-Castillo et al. p.(Thr1771Met) is not one of the exact PM1-eligible hotspot, pathogenic non-hotspot, or uncertain-tier recurrent substitutions, and Cancer Hotspots did not show a statistically significant hotspot at residue T1771.	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 final_classification_framework
PM2	Met	This variant is present at low frequency in population databases, with gnomAD v2.1 AF 3.9888e-05 (0.00399%, 10/250702 alleles) and gnomAD v4.1 AF 4.09054e-05 (0.00409%, 66/1613480 alleles), both below the project's PM2 threshold of 0.1%, with no homozygotes reported.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is a recessive trans-observation criterion, and no qualifying recessive trans observations were identified for this POLE missense variant.
PM4	N/A	This variant is a missense substitution and does not cause a protein length change or an in-frame insertion or deletion, so PM4 is not applicable.	pvs1_variant_assessment
PM5	Not assessed	No evidence was identified for a different pathogenic or likely pathogenic missense change affecting the same amino acid residue Thr1771.	clinvar
PM6	Not assessed	No assumed de novo occurrence data were identified.
PP1	Not assessed	No segregation data were identified to show co-segregation with disease in affected relatives.
PP2	Not assessed	No gene-level evidence was retrieved showing that POLE has a low rate of benign missense variation together with missense variants as a common disease mechanism in a way that would support PP2 for this review.
PP3	Not assessed	The custom POLE PP3 rule requires the exact variant to appear in León-Castillo Supplementary Table S2 or S3 with a REVEL class of 'likely disease causing' and no more than 1 benign in silico result. p.(Thr1771Met) was not found in those tables, so the custom PP3 rule cannot be applied. SpliceAI predicts no significant splice impact (maximum delta score 0.04), and the local REVEL score is 0.178, but a separate generic missense PP3 threshold set was not retrieved.	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 final_classification_framework
PP4	Not assessed	No phenotype-specific clinical presentation or tumor signature evidence was identified that would support a highly specific POLE-associated presentation for this variant.	vcep_p_a_t_h___2_5_0___3_2_3
PP5	N/A	PP5 was not used because assertion-only external classifications are not applied in this review framework.	clinvar
BA1	Not met	Population frequency is below the benign stand-alone threshold: gnomAD v2.1 AF is 0.00399% and gnomAD v4.1 AF is 0.00409%, both well below the BA1 threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency is below the strong benign threshold: gnomAD v2.1 AF is 0.00399% and gnomAD v4.1 AF is 0.00409%, both below the BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in a sufficient number of well-characterized unaffected individuals for BS2.
BS3	Not assessed	No validated variant-specific functional studies were identified showing no damaging effect for p.(Thr1771Met).	oncokb
BS4	Not assessed	No nonsegregation data were identified.
BP1	Not assessed	No gene-specific framework was retrieved supporting BP1 for missense variation in POLE.
BP2	Not assessed	No phase or co-occurrence data were identified to support BP2.
BP3	N/A	BP3 applies to in-frame insertions or deletions in repetitive regions without known function, and this variant is a missense substitution, so BP3 is not applicable.
BP4	Not assessed	The custom POLE BP4 rule requires the exact variant to appear in León-Castillo Supplementary Table S2 or S3 with REVEL class 'Likely benign' or 'Likely-benign' and at least 4 benign in silico results. p.(Thr1771Met) was not found in those tables, so the custom BP4 rule cannot be applied. SpliceAI predicts no significant splice impact (maximum delta score 0.04), and the local REVEL score is 0.178, but a separate generic missense BP4 threshold set was not retrieved.	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 final_classification_framework
BP5	Not assessed	No alternate molecular diagnosis or other variant explaining the phenotype was identified.
BP6	N/A	BP6 was not used because assertion-only external classifications are not applied in this review framework.	clinvar
BP7	N/A	BP7 applies to synonymous or certain intronic variants predicted to have no splicing impact, and this variant is a missense substitution, so BP7 is not applicable.	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.