Submissions for variant NM_000038.6(APC):c.3000C>A (p.Tyr1000Ter)

dbSNP: rs1580629755

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001017988	SCV001179161	pathogenic	Hereditary cancer-predisposing syndrome	2018-06-14	criteria provided, single submitter	clinical testing	The p.Y1000* pathogenic mutation (also known as c.3000C>A), located in coding exon 15 of the APC gene, results from a C to A substitution at nucleotide position 3000. This changes the amino acid from a tyrosine to a stop codon within coding exon 15. This mutation has been reported in 1 of 66 Italian familial adenomatous polyposis (FAP) patients (Giarola M et al. Hum. Mutat., 1999;13:116-23). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004563660	SCV003525891	pathogenic	Familial adenomatous polyposis 1	2022-01-01	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 10094547). ClinVar contains an entry for this variant (Variation ID: 822551). This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Tyr1000*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1844 amino acid(s) of the APC protein.
Myriad Genetics, Inc.	RCV004563660	SCV004044010	pathogenic	Familial adenomatous polyposis 1	2023-05-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.