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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Variant: NM_000038.6(APC):c.423-4del

181781 (ClinVar)

Gene: APC
Condition: familial adenomatous polyposis 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 29a46390-aaf6-4be6-b493-b5a954e33b74
Approved on: 2023-02-18
Published on: 2023-03-14

HGVS expressions

NM_000038.6:c.423-4del
NM_000038.6(APC):c.423-4del

Benign

Met criteria codes 3
BA1 BS3_Supporting BP4
Not Met criteria codes 9
BS1 PVS1 BP1 PS3 PS1 PP3 PP2 PM5 PM2

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP
The c.423-4del variant in APC is an intronic variant which results in the deletion of adenine at position -4 of intron 4. The highest allele frequency is 5.48% in gnomAD v3.1.2, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold for BA1 (≥ 0.1%). RNA assays showed no splicing mutation, indicating that this variant does not impact protein function (BS3_Supporting; PMID22447671). Finally, the results from ≥2 in silico splicing predictors support that this variant does not affect splicing (BP4). 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, BS3_Supporting, BP4. (VCEP specifications version 1; date of approval: 12/12/2022).
Met criteria codes
BA1
The highest population minor allele frequency of the variant c.423-4del in gnomAD v3.1.2 is 0.05478 (2140/39064 alleles) in non-cancer African/African American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis threshold threshold (≥ 0.1%) for BA1, and therefore meets this criterion (BA1).
BS3_Supporting
RNA assays of an APC cDNA fragment spanning from exons 3 to 5 in patient subjects carrying the variant c.423-4del showed no splicing mutation at APC exons 3-5, indicating that this variant does not impact protein function (PMID22447671)(BS3_Supporting).
After analyses of RNA and subsequent PCR amplification and sequence, no exon splices mutations were found at APC exons 3–5 (Supp. Fig. S1). PubMed:22447671
BP4
The results from ≥2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) support that this variant does not affect splicing (BP4).
Not Met criteria codes
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
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
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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