Submissions for variant NM_000038.6(APC):c.423-3_423-2del

dbSNP: rs863225354

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV002519588	SCV003836621	uncertain significance	Familial adenomatous polyposis 1	2023-02-18	reviewed by expert panel	curation	The c.423-3_423-2del p.(?) variant in APC is an intronic variant which deletes two nucleotides at position -2 and -3 in intron 4. This variant has been reported in 3 probands meeting phenotypic criteria, resulting in a total phenotype score of 1.5 (PS4_Supporting; Ambry Genetics, GeneDX and Invitae internal data). In addition, this variant has also been reported in over 20 individuals with a polyposis phenotype not meeting phenotypic criteria. The results from 2 in silico splicing predictors (VarSEAK and MaxEntScan) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 4 of APC, but SpliceAI predicts no impact (PP3 not met). This variant is absent from gnomAD v2.1.1 non-cancer dataset (PM2_Supporting). In summary, this variant is a VUS for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4_Supporting, PM2_Supporting (VCEP specifications version 1; date of approval 12/12/2022).
Invitae	RCV003650456	SCV000552499	pathogenic	Familial adenomatous polyposis 1	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with clinical features of APC-related conditions (PMID: 20223039, 23159591, 33011440; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217982). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 5 and introduces a premature termination codon (PMID: 33011440; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001705159	SCV000567667	likely pathogenic	not provided	2022-10-12	criteria provided, single submitter	clinical testing	In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23159591, 20223039, 28051113, 28152038)
Color Diagnostics, LLC DBA Color Health	RCV000775120	SCV000909229	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-01-06	criteria provided, single submitter	clinical testing	This variant deletes two basepairs, c.423-3_423-2del, in the intron 4 acceptor site of the APC gene. This variant is reported to cause abnormal splicing (ClinVar SCV001183798.3) and two similar variants c.423-5_423-3del (synonymous to c.423-4_423-2del) and c.423-3T>A have been reported to cause an estimated 80% to complete out-of-frame skipping of exon 5, respectively (PMID: 25676610, 33011440). This variant is highly similar to c.423-3T>A in terms of the variant acceptor site and its predicted splicing impact, and it may be reported as this alternate cDNA variant description by external laboratories and databases. The variant creates a premature translational stop signal and is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with colorectal adenoma (PMID: 33436027) and in individuals with clinical diagnosis of familial adenomatous polyposis, attenuated familial adenomatous polyposis or clinical features of APC-related conditions (ClinVar: SCV000552499.7, SCV001183798.3). Similar variants, c.423-3T>A and c.423-3delT have been reported in multiple individuals affected with familial adenomatous polyposis (PMID: 20223039, 30580288; External laboratory communication (ClinVar: SCV000186122.8, SCV000814096.5)) and c.423-3T>A has been reported to segregate with disease in multiple members of a family affected by polyposis or colorectal cancer (PMID: 30580288). This variant has been identified in 1/243264 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV000775120	SCV001183798	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-27	criteria provided, single submitter	clinical testing	The c.423-3_423-2delTA intronic pathogenic mutation results from a deletion of two nucleotides at positions c.423-3 and c.423-2 and involves the canonical splice acceptor site before coding exon 4 of the APC gene. Although In silico splice site analysis for this alteration is inconclusive, RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant has been observed in multiple individuals with a personal and/or family history that is consistent with APC-associated polyposis conditions (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV002519588	SCV004196378	likely pathogenic	Familial adenomatous polyposis 1	2023-10-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000201990	SCV000256992	uncertain significance	not specified		no assertion criteria provided	research