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]
  • Gene label mismatch: APC vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000038.6(APC):c.4735A>T (p.Ile1579Phe)

CA10584253

246402 (ClinVar)

Gene: APC
Condition: familial adenomatous polyposis 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 1f8a9a36-4a8a-4cc6-8eea-1b2497b0e845
Approved on: 2025-05-16
Published on: 2025-05-16

HGVS expressions

NM_000038.6:c.4735A>T
NM_000038.6(APC):c.4735A>T (p.Ile1579Phe)
NC_000005.10:g.112840329A>T
CM000667.2:g.112840329A>T
NC_000005.9:g.112176026A>T
CM000667.1:g.112176026A>T
NC_000005.8:g.112203925A>T
NG_008481.4:g.152809A>T
ENST00000504915.3:c.4789A>T
ENST00000505350.2:c.*4741A>T
ENST00000507379.6:c.4681A>T
ENST00000509732.6:c.4735A>T
ENST00000512211.7:c.4735A>T
ENST00000257430.9:c.4735A>T
ENST00000257430.8:c.4735A>T
ENST00000508376.6:c.4735A>T
ENST00000508624.5:c.*4057A>T
ENST00000520401.1:c.230+11357A>T
NM_000038.5:c.4735A>T
NM_001127510.2:c.4735A>T
NM_001127511.2:c.4681A>T
NM_001354895.1:c.4735A>T
NM_001354896.1:c.4789A>T
NM_001354897.1:c.4765A>T
NM_001354898.1:c.4660A>T
NM_001354899.1:c.4651A>T
NM_001354900.1:c.4612A>T
NM_001354901.1:c.4558A>T
NM_001354902.1:c.4462A>T
NM_001354903.1:c.4432A>T
NM_001354904.1:c.4357A>T
NM_001354905.1:c.4255A>T
NM_001354906.1:c.3886A>T
NM_001127510.3:c.4735A>T
NM_001127511.3:c.4681A>T
NM_001354895.2:c.4735A>T
NM_001354896.2:c.4789A>T
NM_001354897.2:c.4765A>T
NM_001354898.2:c.4660A>T
NM_001354899.2:c.4651A>T
NM_001354900.2:c.4612A>T
NM_001354901.2:c.4558A>T
NM_001354902.2:c.4462A>T
NM_001354903.2:c.4432A>T
NM_001354904.2:c.4357A>T
NM_001354905.2:c.4255A>T
NM_001354906.2:c.3886A>T
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Uncertain Significance

Met criteria codes 4
BP1 PS4_Supporting PM2_Supporting PS3_Supporting

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP
The NM_000038.6(APC):c.4735A>T variant in APC is a missense variant predicted to cause substitution of Isoleucine by Phenylalanine at amino acid position 1579 (p.Ile1579Phe). β-catenin regulated transcription activity assay in SW480 cells showed increased β-catenin regulated transcription activity indicating that this variant impacts protein function (PS3_Supporting, PMID: 18199528). This variant has been reported in 3 probands meeting phenotypic criteria, resulting in a total phenotype score of 1.5 points (PS4_Supporting [Ambry Genetics, Invitae, GeneDx]). The variant has been reported in 1 additional proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (Ambry Genetics). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). APC, in which the variant was identified, is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this variant is a VUS for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BP1, PS3_Supporting, PS4_Supporting, PM2_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023).
Met criteria codes
BP1
APC, in which the variant was identified, is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1).
PS4_Supporting
This variant has been reported in 3 probands meeting phenotypic criteria, resulting in a total phenotype score of 1.5 points (PS4_Supporting [Ambry Genetics, Invitae, GeneDx]). The variant has been reported in 1 additional proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (Ambry Genetics).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PS3_Supporting
β-catenin regulated transcription activity assay in SW480 cells showed increased β-catenin regulated transcription activity indicating that this variant impacts protein function (PS3_Supporting, PMID: 18199528).
β-catenin regulated transcription activity assay PubMed:18199528
Curation History
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