Variant: NM_000038.6(APC):c.532-8G>A

CA16611747

411469 (ClinVar)

Gene: APC

Condition: familial adenomatous polyposis 1

Inheritance Mode: Autosomal dominant inheritance

UUID: ce50ff0f-3705-41a6-81a6-1ad20b3b3a2b

Approved on: 2023-02-18

Published on: 2023-03-14

HGVS expressions

NM_000038.6:c.532-8G>A
NM_000038.6(APC):c.532-8G>A
NC_000005.10:g.112780782G>A
CM000667.2:g.112780782G>A
NC_000005.9:g.112116479G>A
CM000667.1:g.112116479G>A
NC_000005.8:g.112144378G>A
NG_008481.4:g.93262G>A
ENST00000257430.9:c.532-8G>A
ENST00000257430.8:c.532-8G>A
ENST00000507379.5:c.562-8G>A
ENST00000508376.6:c.532-8G>A
ENST00000508624.5:c.532-8G>A
ENST00000512211.6:c.532-8G>A
NM_000038.5:c.532-8G>A
NM_001127510.2:c.532-8G>A
NM_001127511.2:c.562-8G>A
NM_001354895.1:c.532-8G>A
NM_001354896.1:c.532-8G>A
NM_001354897.1:c.562-8G>A
NM_001354898.1:c.457-8G>A
NM_001354899.1:c.532-8G>A
NM_001354900.1:c.355-8G>A
NM_001354901.1:c.355-8G>A
NM_001354902.1:c.562-8G>A
NM_001354903.1:c.532-8G>A
NM_001354904.1:c.457-8G>A
NM_001354905.1:c.355-8G>A
NM_001354906.1:c.-504-8G>A
NM_001127510.3:c.532-8G>A
NM_001127511.3:c.562-8G>A
NM_001354895.2:c.532-8G>A
NM_001354896.2:c.532-8G>A
NM_001354897.2:c.562-8G>A
NM_001354898.2:c.457-8G>A
NM_001354899.2:c.532-8G>A
NM_001354900.2:c.355-8G>A
NM_001354901.2:c.355-8G>A
NM_001354902.2:c.562-8G>A
NM_001354903.2:c.532-8G>A
NM_001354904.2:c.457-8G>A
NM_001354905.2:c.355-8G>A
NM_001354906.2:c.-504-8G>A

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PS4_Moderate PM2_Supporting PS3 PP3

Expert Panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Criteria Specification Information

Evidence submitted by expert panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

The c.532-8G>A variant in APC is an intronic variant which is located 8 nucleotides upstream of the splice acceptor site for exon 6. This variant has been reported in 3 families meeting phenotypic criteria, resulting in a total phenotype score of 2.5 (PS4_Moderate; Ambry internal data; Invitae internal data; Leiden, Bonn, PMID 24599579; PMID19196998). This variant is absent from gnomAD v2.1.1 (PM2_supporting). The results from ≥2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 5 of APC (PP3). RT-PCR and minigene assay demonstrate that this variant impacts splicing by creating a novel splice acceptor site six nucleotides upstream of the regular splice acceptor site of exon 6 which results in the inclusion of six nucleotides including a premature termination codon. A complete splice defect was confirmed using transcript-specific PCR and SNP analysis of c.1458T>C (PS3_VeryStrong; PMID 19196998). 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: PS3_VeryStrong; PS4_moderate; PM2_supporting; PP3 (VCEP specifications version 1; date of approval: 12/12/2022).

Met criteria codes

• PS4_Moderate: This variant has been reported in 3 families meeting phenotypic criteria, resulting in a total phenotype score of 2.5 (PS4_Moderate; Ambry internal data; Invitae internal data; Leiden, Bonn, PMID 24599579; PMID19196998).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PS3: RT-PCR and minigene assay demonstrated that this variant impacts splicing by creating a novel splice acceptor site 6 nucleotides upstream of exon 6 which is included in the transcript and also encodes a premature termination codon. A complete splice defect was confirmed using transcript-specific PCR and SNP analysis of c.1458T/C (PMID 19196998) (PS3_VeryStrong).
• PP3: The results from ≥2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 5 of APC (PP3).