Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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  • See Evidence submitted by expert panel for details.

Variant: NM_000038.6(APC):c.4420G>A (p.Ala1474Thr)

133530 (ClinVar)

Gene: APC
Condition: familial adenomatous polyposis 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 84be63ca-6205-415b-8aa7-b32b28a56daf
Approved on: 2023-02-26
Published on: 2023-03-14

HGVS expressions

NM_000038.6:c.4420G>A
NM_000038.6(APC):c.4420G>A (p.Ala1474Thr)

Benign

Met criteria codes 3
BS3_Supporting BP1 BA1
Not Met criteria codes 4
PM2 BP4 PS3 PP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP
The c.4420G>A variant in APC is a missense variant predicted to cause the substitution of Alanine by Threonine at amino acid position 1474 (p.Ala1474Thr). The highest population minor allele frequency of this variant in gnomAD v2.1.1 (non-cancer) is 1.13% in the African/African American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel’s (HCCP VCEP) threshold (≥ 0.1%) for BA1, and therefore meets this criterion (BA1). Functional study of β-catenin-regulated transcription assays indicate that this alteration suppresses CRT as effectively as wild type (BS3_Supporting; PMID: 18199528). Finally, APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1, BP1, BS3_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).
Met criteria codes
BS3_Supporting
Functional study of β-catenin-regulated transcription assays indicated that this alteration suppressed CRT as effectively as wild type (PubMed:18199528, BS3_Supporting).
BP1
APC, in which the variant was identified, is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP as a gene for which primarily truncating variants are known to cause disease (BP1).
BA1
The highest population minor allele frequency (non-cancer) in gnomAD v2.1.1 is 1.131% in the African/African American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis threshold (≥ 0.1%) for BA1, and therefore meets this criterion (BA1).
Not Met criteria codes
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
Multiple lines of computational evidence suggest no splicing impact (SpliceAI and varSEAK).
Curation History
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