Variant classification summary

NM_006231.4:c.2413C>T

POLE · NP_006222.2:p.(Gln805Ter) · NM_006231.4

GRCh37: chr12:133241943 G>A · GRCh38: chr12:132665357 G>A

Gene: POLE Transcript: NM_006231.4

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Gln805Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: c.2413C>T creates the premature stop p.(Gln805Ter) in exon 21 of 49 with predicted nonsense-mediated decay, a null allele in a gene where biallelic loss of function causes FILS and IMAGe syndromes.

2

PM2 moderate: the variant is absent from every reporting population dataset (gnomAD-Canada v1.0 zero alleles; no gnomAD frequency), consistent with extreme rarity for a recessive-disease truncating allele.

Final determination: The Leon-Castillo et al. 2020 custom POLE framework's likely-pathogenic combination rule 'PVS1_VeryStrong + 1 Moderate' is satisfied by PVS1 (very strong) together with PM2 (moderate), with no met benign criterion, yielding Likely Pathogenic under standard ACMG/AMP 2015 final-combination logic.

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	Met	Met at Very Strong: c.2413C>T introduces premature stop p.(Gln805Ter) in exon 21 of 49 (MANE Select) with predicted NMD; biallelic POLE loss-of-function causes FILS/IMAGe syndromes.	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework vcep_path_250_323 PMID:23230001 PMID:25948378 PMID:30503519 gnomad_canada
PS1	N/A	Not applicable: p.(Gln805Ter) is a nonsense change, and no alternative nucleotide change can produce the same stop for PS1's same-amino-acid comparison.	pvs1_variant_assessment clinvar pm5_candidates
PS2	Not assessed	Not assessed: no source reports c.2413C>T (p.Gln805Ter) as de novo, none of the three POLE papers mentions this variant, and no parental genotyping data exist.	generic_acmg_combination_rules clinvar PMID:23230001 PMID:25948378 PMID:30503519
PS3	Not assessed	Not assessed: no well-established functional assay of p.Q805* exists - OncoKB lists no reviewed functional data and none of the three full-text papers mentions the variant.
PS4	Not met	Not met: no case-control or recurrence enrichment exists for c.2413C>T; it falls outside the custom POLE PS4 set of exonuclease missense hotspots (COSMIC+TCGA count >=10).	vcep_path_250_323 vcep_path_250_323_s002 clinvar PMID:23230001 PMID:25948378 PMID:30503519
PM1	Not met	Not met: p.(Gln805Ter) is not a listed POLE exonuclease-domain hotspot substitution (framework residues 278-465), and no domain table or CancerHotspots signal places Q805 in a critical domain.	final_classification_framework vcep_path_250_323
PM2	Met	Met: c.2413C>T (p.Gln805Ter) is absent from gnomAD-Canada v1.0 and reported absent from gnomAD, supporting PM2 extreme rarity in population controls.	gnomad_canada clinvar
PM3	Not assessed	Not assessed: c.2413C>T (p.Gln805Ter) is reported nowhere in trans with a pathogenic POLE allele; the sole ClinVar submission and all three full-text papers lack proband phase data.	generic_acmg_combination_rules clinvar PMID:23230001 PMID:25948378 PMID:30503519
PM4	N/A	Not applicable: PM4 covers in-frame deletions/insertions and stop-loss changes; this nonsense substitution p.(Gln805Ter) is a truncating null event adjudicated under PVS1.
PM5	N/A	Not applicable: PM5 requires a novel missense change at a residue with a known pathogenic missense; p.(Gln805Ter) is a nonsense variant and no same-residue comparator exists.	pvs1_variant_assessment pm5_candidates clinvar
PM6	Not assessed	Not assessed: no assumed-de novo occurrence of c.2413C>T (p.Gln805Ter) is reported anywhere, and proband-parental genotyping data for this variant are absent.	generic_acmg_combination_rules clinvar PMID:23230001 PMID:25948378 PMID:30503519
PP1	Not assessed	Not assessed: no affected family members carrying c.2413C>T (p.Gln805Ter) are reported, so no segregating meioses exist to score for PP1.	generic_acmg_combination_rules clinvar PMID:23230001 PMID:25948378 PMID:30503519
PP2	N/A	Not applicable: PP2 evaluates missense variants in genes where missense is a common mechanism; p.(Gln805Ter) is a truncating nonsense change, not missense.	pvs1_variant_assessment vcep_path_250_323
PP3	N/A	Not applicable: c.2413C>T is a nonsense change (p.Gln805Ter), and PP3 is calibrated only for missense or splice-region variants, not truncating ones.	final_classification_framework generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family history is available, so specificity for a POLE-related disorder (FILS/IMAGe, biallelic loss-of-function) cannot be evaluated.	clinvar PMID:23230001 PMID:25948378 PMID:30503519
PP5	Not met	Not met: ClinVar holds a single one-star laboratory submission for c.2413C>T, and PP5 requires an exact-variant expert-panel Pathogenic/Likely pathogenic classification.	clinvar
BA1	Not met	Not met: c.2413C>T is absent from every population dataset reporting an allele count (gnomAD-Canada v1.0), an allele frequency of zero far below the BA1 stand-alone threshold.	gnomad_canada clinvar
BS1	Not met	Not met: observed allele frequency is zero (absent from gnomAD-Canada v1.0; no gnomAD frequency), far below any frequency exceeding expectation for an ultra-rare recessive syndrome.	gnomad_canada clinvar
BS2	Not met	Not met: no healthy adult, homozygous or heterozygous, has been observed with c.2413C>T in any control or population dataset (absent from gnomAD-Canada v1.0).	gnomad_canada
BS3	Not assessed	Not assessed: no functional assay data on p.Q805* in either direction; no validated study shows the variant preserves POLE function.
BS4	Not assessed	Not assessed: no affected relatives have been genotyped for c.2413C>T (p.Gln805Ter), so absence of segregation (BS4) cannot be established or refuted.	generic_acmg_combination_rules clinvar PMID:23230001 PMID:25948378 PMID:30503519
BP1	N/A	Not applicable: BP1 applies only to missense variants in primarily truncating genes; p.(Gln805Ter) is itself a truncating nonsense allele, and POLE missense is an established mechanism.	pvs1_variant_assessment vcep_path_250_323 PMID:23230001 PMID:25948378 PMID:30503519
BP2	Not assessed	Not assessed: no source reports c.2413C>T in cis (or trans for dominant disease) with a pathogenic POLE variant; heterozygous truncating-allele carriers are unaffected, so only cis-observation evidence could apply BP2.	generic_acmg_combination_rules clinvar PMID:23230001 PMID:25948378 PMID:30503519
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region without known function; c.2413C>T is a single-nucleotide nonsense substitution, not an indel.
BP4	N/A	Not applicable: c.2413C>T is a nonsense change (p.Gln805Ter); BP4 likewise covers only missense or splice-region variants, never truncating ones.	final_classification_framework generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternate molecular basis for disease was identified or documented for the proband, which BP5 requires.
BP6	Not met	Not met: ClinVar has no expert-panel Benign/Likely benign classification for c.2413C>T; the sole one-star laboratory Pathogenic submission cannot trigger BP6.	clinvar
BP7	N/A	Not applicable: BP7 is reserved for synonymous variants, but c.2413C>T creates a stop codon (p.Gln805Ter) instead.

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