NM_000038.6:c.3927_3931del

816 (ClinVar)

Gene: APC

Condition: familial adenomatous polyposis 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 296f1801-94a5-465b-9e48-8c839bf73039

HGVS expressions

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

Pathogenic

• Met criteria codes: PM6_Strong PVS1 PS4

• Not Met criteria codes: PM2

Expert Panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Criteria Specification Information

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.

Approved on: 2023-02-25

Published on: 2023-03-14