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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816 (ClinVar)

Gene: APC
Condition: familial adenomatous polyposis 1
Inheritance Mode: Autosomal dominant inheritance
UUID: 296f1801-94a5-465b-9e48-8c839bf73039
Approved on: 2023-02-25
Published on: 2023-03-14

HGVS expressions

NM_000038.6:c.3927_3931del
NM_000038.6(APC):c.3927_3931del (p.Glu1309fs)

Pathogenic

Met criteria codes 3
PM6_Strong PVS1 PS4
Not Met criteria codes 1
PM2

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.3927_3931del (p.Glu1309Aspfs*4) variant in APC is a variant predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in more than 400 probands, resulting in a total phenotype score of 33 (PS4_VeryStrong, GeneDx, Ambry, Invitae, Catalan Institute of Oncology, University Hospital of Bonn, Leiden University Medical Center internal data). It has also been identified as a de novo occurrence with unconfirmed parental relationships in 63 individuals on LOVD and in 4 individuals from Barcelona internal data, the total points scored based on available phenotypic information is 17.5 (PM6_VeryStrong, LOVD, Catalan Institute of Oncology internal data). The highest allele frequency of this variant gnomAD v2.1.1 (non-cancer) is 0.000008456, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold of ≤ 0.000003 for PM2_Supporting (PM2_Supporting not met) and lower than the threshold (≥0.00001) for BS1 (BS1 not met). It is the most common pathogenic APC variant in APC InSiGHT LOVD (www.lovd.nl/APC; 331 / 5700 = 5.8%; retrieved on 06/01/2023), thus the occurrence in gnomAD is compatible with a pathogenic variant. In summary, this variant meets the criteria to be classified as Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PVS1, PS4_VeryStrong, and PM6_VeryStrong (VCEP specifications version 1; date of approval: 12/12/2022).
Met criteria codes
PM6_Strong
This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 63 individual on LOVD and in 4 individual from Barcelona, the total points scored based on available phenotypic information is 17.5 (PM6_very strong, LOVD, Catalan Institute of Oncology).
PVS1
The c.3927_3931del (p.Glu1309AspfsTer4) variant in APC is a variant predicted/observed to cause a premature stop codon in biologically-relevant-exon 15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
PS4
This variant has been reported in more than 400 probands, resulting in a total phenotype score of 33 (PS4_very strong, GeneDx, Ambry, Invitae, Catalan Institute of Oncology, University Hospital of Bonn, Leiden University Medical Center)
Not Met criteria codes
PM2
The highest population minor allele frequency of the variant c.3927_3931del in gnomAD v2.1.1 (non-cancer) is 0.000008456 (2/236524 alleles) in the Total population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis threshold threshold (≤ 0.000003) for PM2_supporting.
Curation History
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