Submissions for variant NM_000038.6(APC):c.3786T>A (p.Tyr1262Ter)

dbSNP: rs147411334

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001243559	SCV001416727	pathogenic	Familial adenomatous polyposis 1	2019-11-16	criteria provided, single submitter	clinical testing	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. For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed in individual(s) with familial adenomatous polyposis (PMID: 11247896, 17411426). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the APC gene (p.Tyr1262*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1582 amino acids of the APC protein.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001243559	SCV001553337	pathogenic	Familial adenomatous polyposis 1		no assertion criteria provided	clinical testing	The APC p.Tyr1262* variant was identified in 2 of 1508 proband chromosomes (frequency: 0.001) from individuals or families with Familial adenomatous polyposis (Friedl 2001, Stekrova 2007). The variant was also identified in LOVD 3.0 (2x as pathogenic). In addition, another variant, c.3786T>G at the same position with different nucleotide change and same amino acid change, p.Tyr1262* was found in Clinvar and was classified as pathogenic. The c.3786T>A variant was not identified in dbSNP, ClinVar, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3786T>A variant leads to a premature stop codon at position 1262 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in APC associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.