Variant classification summary

NM_000038.6:c.2677G>A

APC · NP_000029.2:p.(Glu893Lys) · NM_000038.6

GRCh37: chr5:112173968 G>A · GRCh38: chr5:112838271 G>A

Gene: APC Transcript: NM_000038.6

Final call

VUS

BP1 supporting

Variant details

Gene

APC

Transcript

NM_000038.6

Protein

NP_000029.2:p.(Glu893Lys)

gnomAD AF

2.230345083947711e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP1 supporting: APC codon 893 lies outside the VCEP exception at codons 1021-1035.

Final determination: Under the APC InSiGHT VCEP Version 2.1 criteria-combination framework, BP1 supporting alone does not satisfy any pathogenic, likely pathogenic, likely benign, or benign rule, so the final call is VUS.

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	Not applicable: NM_000038.6:c.2677G>A produces p.Glu893Lys, a missense substitution rather than a nonsense, frameshift, or canonical splice loss-of-function variant.	cspec vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 pvs1_variant_assessment
PS1	Not met	Not met: the APC specification identifies only p.Asn1026Ser and p.Ser1028Arg as likely pathogenic missense comparators, not p.Glu893Lys.	cspec
PS2	Not assessed	Not assessed: no documented parental genotypes, confirmed maternity and paternity, affected phenotype, or APC VCEP de novo score is available.	cspec clinvar
PS3	Not assessed	Not assessed: no variant-specific RNA or validated damaging protein assay was identified for p.(Glu893Lys), which lies outside the APC beta-catenin-binding domain at codons 959-2129.	cspec oncokb PMID:25741868 PMID:22703879
PS4	Not assessed	Not assessed: no exact-variant case-control enrichment or patient phenotype-point data are available to compare with the APC VCEP PS4 thresholds.	cspec PMID:15604628 PMID:25394175 PMID:22703879
PM1	N/A	Not applicable: the APC VCEP explicitly marks PM1 as not applicable, and its authoritative APC domain table contains no entries.	cspec
PM2	Not assessed	Not assessed: the VCEP requires non-cancer AF, while only combined values of 2.39238e-05 and 2.23035e-05 are available.	cspec
PM3	N/A	Not applicable: the APC VCEP excludes PM3 because APC-associated familial adenomatous polyposis is autosomal dominant, not recessive.	cspec
PM4	N/A	Not applicable: the APC VCEP does not use PM4 because data for protein-length changes are limited, and this variant causes no protein-length change.	cspec vcep_apc_specifications_supplementary_material_v2
PM5	Not assessed	Not assessed: zero same-residue candidates were found, but the comparator search recorded an HTTP 429 error and cannot exclude a qualifying p.Glu893 variant.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no assumed-de-novo observation, phenotype point, parental testing status, or APC VCEP de novo score is documented.	cspec clinvar
PP1	Not assessed	Not assessed: no affected relatives, variant-positive family members, family count, or segregating meiosis count is documented.	cspec clinvar
PP2	N/A	Not applicable: the APC VCEP explicitly excludes PP2 for APC missense variants.	cspec
PP3	Not met	Not met: missense REVEL 0.617 is below the >=0.644 supporting PP3 threshold, and the SpliceAI score cannot substitute for the applicable REVEL path.	cspec revel
PP4	N/A	Not applicable: the APC VCEP marks PP4 unavailable because phenotype specificity is captured by its PS4 phenotype-point system.	cspec
PP5	N/A	Not applicable: the APC VCEP excludes PP5, and this exact variant has no ClinVar expert-panel Pathogenic or Likely pathogenic classification.	cspec clinvar
BA1	Not assessed	Not assessed: the APC VCEP requires non-cancer Popmax AF, but only all-comers values (2.302e-05 and 1.994e-05) are available.	cspec
BS1	Not assessed	Not assessed: the APC VCEP requires non-cancer Popmax AF, although available all-comers values (2.302e-05 and 1.994e-05) exceed 0.00001.	cspec
BS2	Not assessed	Not assessed: no qualifying healthy individuals or VCEP-required non-cancer homozygote count is available; combined datasets report zero homozygotes but are not sufficient.	cspec
BS3	Not assessed	Not assessed: p.(Glu893Lys) is a codon-893 missense variant with no qualifying benign RNA or protein assay under the APC VCEP BS3 requirements.	cspec oncokb PMID:25741868 PMID:22703879
BS4	Not assessed	Not assessed: no affected relative lacking the variant has a documented APC phenotype point of at least 0.5.	cspec clinvar
BP1	Met	Met, supporting: APC codon 893 lies outside the VCEP BP1 exception at codons 1021-1035.	cspec
BP2	Not assessed	Not assessed: no qualifying trans observation or at least three unknown-phase observations with different (Likely) Pathogenic APC variants are documented.	cspec
BP3	N/A	Not applicable: the APC VCEP designates BP3 as not applicable, and p.Glu893Lys is a missense substitution rather than an in-frame length change in a repeat region.	cspec vcep_apc_specifications_supplementary_material_v2
BP4	N/A	Not applicable: the APC VCEP explicitly excludes BP4 for missense variants, regardless of the available SpliceAI max delta 0.002.	cspec
BP5	Not assessed	Not assessed: no alternate-gene Pathogenic/Likely pathogenic variant and no documented colorectal-polyposis phenotype are available for the APC VCEP BP5 rule.	cspec clinvar
BP6	N/A	Not applicable: the APC VCEP excludes BP6, and the exact variant has no ClinVar expert-panel Benign or Likely benign classification.	cspec clinvar
BP7	N/A	Not applicable: this is a missense p.Glu893Lys variant, whereas BP7 is restricted to synonymous variants under the APC VCEP rule.	cspec

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