Variant classification summary

NM_001127510.3:c.7594C>T

APC · NP_001120982.1:p.(His2532Tyr) · NM_001127510.3

GRCh37: chr5:112178885 C>T · GRCh38: chr5:112843188 C>T

Gene: APC Transcript: NM_001127510.3

Final call

Likely Benign

BS1 strong BP1 supporting

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(His2532Tyr)

gnomAD AF

1.3637034217798313e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1 strong: gnomAD v4.1 Popmax FAF of 1.064e-05 exceeds the APC VCEP threshold of 1e-05.

2

BP1 supporting: residue 2532 lies outside the APC VCEP exception at codons 1021-1035.

Final determination: Under Rule26 of the ClinGen InSiGHT APC Version 2.1 framework, one BS1/BS2/BS3/BS4 criterion at strong strength maps to Likely Benign; BS1 strong satisfies this rule.

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: c.7594C>T is a missense variant, not an APC nonsense, frameshift, or canonical ±1,2 splice null variant covered by PVS1.	cspec vcep_fig_1_apc_pvs1_decision_tree_2023_10_20
PS1	Not met	Not met: p.(His2532Tyr) does not match either VCEP-listed likely pathogenic APC missense change, p.(Asn1026Ser) or p.(Ser1028Arg).	cspec pm5_candidates
PS2	Not assessed	Not assessed: no proband-level parental testing or phenotype-based de novo score is available to compare with the APC VCEP threshold of >=1 score.	cspec vcep_table_1_262
PS3	Not assessed	Not assessed: APC VCEP requires damaging RNA or protein assay evidence, but no variant-specific functional assay result is available for p.His2532Tyr.	cspec oncokb
PS4	Not assessed	Not assessed: no curated phenotype-point total, case-control enrichment estimate, or sufficient unrelated affected-person phenotype data is available for this exact variant.	cspec vcep_table_1_262
PM1	N/A	Not applicable: the governing APC VCEP explicitly designates PM1 as not applicable for APC variant interpretation.	cspec
PM2	Not met	Not met: non-cancer gnomAD v2.1 exomes show AF 1.27043e-05 with allele count 3, above the APC PM2 threshold of 3e-06.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the APC VCEP excludes PM3 because familial adenomatous polyposis has autosomal-dominant inheritance.	cspec
PM4	N/A	Not applicable: APC VCEP Version 2.1 excludes PM4, and p.(His2532Tyr) does not change protein length.	cspec vcep_apc_specifications_supplementary_material_v2
PM5	Not assessed	Not assessed: no p.His2532 comparator was verified, and comparator retrieval ended with HTTP 429 before absence could be established.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no assumed-de-novo parental testing result or de novo score is available to compare with the APC VCEP threshold of 0.5 score.	cspec vcep_table_1_262
PP1	Not assessed	Not assessed: no affected relatives, family segregation data, or informative meiosis count is available to compare with the APC VCEP minimum of 3 meioses.	cspec
PP2	N/A	Not applicable: the governing APC VCEP explicitly designates PP2 as not applicable for APC missense variants.	cspec
PP3	Not met	Not met: REVEL 0.452 is below the calibrated supporting PP3 threshold of 0.644 for this missense variant.	cspec revel
PP4	N/A	Not applicable: the APC VCEP explicitly excludes PP4 because phenotype and family-history evidence is captured under PS4.	cspec
PP5	N/A	Not applicable: the APC VCEP excludes PP5, and ClinVar has zero exact-variant expert-panel Pathogenic or Likely pathogenic classifications.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 Popmax FAF is 1.064e-05, below the APC VCEP BA1 threshold of 0.001.	cspec gnomad_v4
BS1	Met	Met, strong: gnomAD v4.1 Popmax FAF is 1.064e-05, exceeding the APC VCEP BS1 threshold of 1e-05.	cspec gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 0 homozygotes, but no individual-level healthy-control data are available to calculate the APC VCEP point thresholds.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: APC VCEP requires a qualifying no-effect RNA or β-catenin transcription assay, but no variant-specific benign functional result is available.	cspec oncokb
BS4	Not assessed	Not assessed: no affected noncarrier or phenotype-point score is available to compare with the APC VCEP BS4 threshold of 0.5 phenotype points.	cspec vcep_table_1_262
BP1	Met	Met, Supporting: APC residue 2532 lies outside the VCEP BP1 exception at codons 1021-1035 in the beta-catenin-binding domain.	cspec
BP2	Not assessed	Not assessed: no documented trans observation, second pathogenic APC variant, phase result, or qualifying three-variant recurrence is available.	cspec
BP3	N/A	Not applicable: APC VCEP Version 2.1 excludes BP3, and p.(His2532Tyr) is not an in-frame indel in a repetitive region.	cspec vcep_apc_specifications_supplementary_material_v2
BP4	N/A	Not applicable: the APC VCEP explicitly excludes BP4 for missense variants such as p.(His2532Tyr).	cspec
BP5	Not assessed	Not assessed: no qualifying alternate pathogenic gene finding and no documented colorectal polyposis phenotype are available for BP5.	cspec
BP6	N/A	Not applicable: the APC VCEP excludes BP6, and ClinVar has zero exact-variant expert-panel Benign or Likely benign classifications.	cspec clinvar
BP7	N/A	Not applicable: BP7 is limited to synonymous or qualifying intronic variants, whereas this variant is missense p.(His2532Tyr).	cspec

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.