NM_000038.6:c.509_512del

804 (ClinVar)

Gene: APC

Condition: familial adenomatous polyposis 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 80cd255c-1080-43ea-9aa9-61e2d39fd0c4

Approved on: 2023-02-18

Published on: 2023-03-14

HGVS expressions

NM_000038.6:c.509_512del
NM_000038.6(APC):c.509_512del (p.Asp170fs)

Pathogenic

• Met criteria codes: PS4 PVS1 PP1_Moderate PM2_Supporting

Expert Panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Criteria Specification Information

Evidence submitted by expert panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

The c.509_512del (p.Asp170Valfs*4) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 5 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in > 8 probands meeting phenotypic criteria, resulting in a total phenotype score of 5 (PS4, PMID 1324223, Ambry Genetics, Invitae, Leiden, Bonn, Melbourne internal data). In addition, this variant has been reported to segregate with FAP in > 10 affected meioses in 1 family (PP1_Moderate; PMID 1324223). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1, PS4, PM2_Supporting, PP1_Moderate (VCEP specifications version 1; date of approval: 12/12/2022).

Met criteria codes

• PS4: This variant has been reported in > 8 probands meeting phenotypic criteria, resulting in a total phenotype score of 5 (PS4, PMID 1324223, Ambry Genetics, Invitae, Leiden, Bonn, Melbourne internal data).
• PVS1: The c.509_512del p.(Asp170Valfs*4) (NM_000038.6) variant in APC is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 5 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PP1_Moderate: This variant has been reported to segregate with FAP in > 10 affected meioses in 1 family (PP1_Moderate; PMID 1324223).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).