Variant classification summary

NM_001127510.3:c.1631T>C

APC · NP_001120982.1:p.(Ile544Thr) · NM_001127510.3

GRCh37: chr5:112164557 T>C · GRCh38: chr5:112828860 T>C

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.(Ile544Thr)

gnomAD AF

0.0002336055616812125 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BS1 is strong because gnomAD v4.1 grpmax FAF exceeds the APC VCEP frequency threshold.

2

Likely Benign: BP1 is supporting because codon 544 lies outside the APC VCEP's beta-catenin-binding repeat exception.

Final determination: APC VCEP Rule26 assigns Likely Benign when one strong benign criterion such as BS1 is met; BS1 strong therefore determines the final call.

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.1631T>C produces the missense substitution p.Ile544Thr rather than a nonsense, frameshift, or canonical splice-null consequence.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	Not met: the APC VCEP's two recognized likely pathogenic missense comparators are p.Asn1026Ser and p.Ser1028Arg, not p.Ile544Thr.	cspec PMID:23159591
PS2	Not assessed	Not assessed: the variant was reported in one individual, but no parental testing, confirmed maternity or paternity, or phenotype-point data are available to calculate a de novo score.	cspec PMID:23159591
PS3	Not assessed	Not assessed: no variant-specific RNA or protein functional assay result is available to meet the APC VCEP PS3 requirements.	cspec PMID:23159591
PS4	Not assessed	Not assessed: the exact variant was seen once, but no phenotype-point score or case-control enrichment data are available for the APC PS4 thresholds.	cspec vcep_table_1_262 PMID:23159591
PM1	N/A	Not applicable: the governing APC VCEP explicitly designates PM1 as not applicable, and no APC domain-table entry is available to alter that rule.	cspec vcep_apc_specifications_supplementary_material_v2
PM2	Not met	Not met: gnomAD v4.1 AF 0.000233606 with allele count 375 exceeds the APC PM2 threshold of 0.000003.	cspec gnomad_v4
PM3	N/A	Not applicable: the APC VCEP excludes PM3 because familial adenomatous polyposis is autosomal dominant, not recessive.	cspec
PM4	N/A	Not applicable: p.Ile544Thr is a missense substitution, not a protein-length change caused by an in-frame deletion or insertion.	cspec
PM5	Not assessed	Not assessed: zero codon-544 comparator candidates were collected, but the PM5 search ended with an HTTP 429 rate-limit error, so absence of a qualifying alternate cannot be confirmed.	cspec pm5_candidates PMID:23159591
PM6	Not assessed	Not assessed: one reported individual is insufficient because no assumed-de-novo documentation, parental relationship evidence, or phenotype-point data are provided.	cspec PMID:23159591
PP1	Not assessed	Not assessed: no affected relatives, informative pedigree, segregation results, or meiosis count are reported for the variant.	cspec PMID:23159591
PP2	N/A	Not applicable: the APC VCEP explicitly excludes PP2 because missense variants are not a frequent disease mechanism in APC.	cspec vcep_apc_specifications_supplementary_material_v2
PP3	Not met	Not met: SpliceAI maximum delta 0.001 is below the 0.2 supporting threshold and does not support a deleterious splice effect.	cspec spliceai
PP4	N/A	Not applicable: the APC VCEP states that PP4 is not applicable because phenotype specificity is captured by its PS4 phenotype-point system.	cspec
PP5	N/A	Not applicable: the APC VCEP excludes PP5, and ClinVar shows zero expert-panel submissions for this exact variant.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 Popmax-related frequency 0.000304574 (0.03046%) is below the APC BA1 threshold of 0.001 (0.1%).	cspec gnomad_v4
BS1	Met	Met, strong: gnomAD v4.1 grpmax FAF 0.00027828 exceeds the APC BS1 threshold of 0.00001 (0.001%).	cspec gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 reports 0 homozygotes, and no qualifying healthy-individual points or 2 homozygous observations are documented.	cspec gnomad_v4 PMID:23159591
BS3	Not assessed	Not assessed: no variant-specific benign RNA or protein assay result, including required controls, is available to meet the APC VCEP BS3 requirements.	cspec PMID:23159591
BS4	Not assessed	Not assessed: no affected relatives without the variant or phenotype-point evidence is available to demonstrate non-segregation.	cspec PMID:23159591
BP1	Met	Met (Supporting): p.Ile544Thr is at codon 544, outside the APC VCEP BP1 exception for codons 1021-1035 in the beta-catenin-binding repeat.	cspec vcep_apc_specifications_supplementary_material_v2
BP2	Not assessed	Not assessed: the variant was reported once, but no pathogenic partner variant or cis/trans phase information establishes the APC BP2 threshold.	cspec PMID:23159591
BP3	N/A	Not applicable: c.1631T>C is a missense substitution, not an in-frame deletion or insertion subject to the BP3 repeat-region criterion.	cspec
BP4	N/A	Not applicable: the APC VCEP explicitly excludes missense variants from BP4, which is reserved for synonymous or intronic variants.	cspec
BP5	Not assessed	Not assessed: no qualifying alternate pathogenic gene variant and no documented colorectal polyposis phenotype are available for the exact APC variant case.	cspec
BP6	N/A	Not applicable: the APC VCEP excludes BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign assertion.	cspec clinvar
BP7	N/A	Not applicable: c.1631T>C produces p.(Ile544Thr), so this is a missense rather than a synonymous variant.	cspec

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