Submissions for variant NM_000038.6(APC):c.1246dup (p.Tyr416fs) (rs1060503366)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000468001	SCV000552751	pathogenic	Familial adenomatous polyposis 1	2017-04-21	criteria provided, single submitter	clinical testing	This sequence change inserts 1 nucleotide in exon 10 of the APC mRNA (c.1246dupT), causing a frameshift at codon 416. This creates a premature translational stop signal (p.Tyr416Leufs*3) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in APC are known to be pathogenic (PMID: 20685668, 17963004). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc	RCV000659273	SCV000781070	likely pathogenic	Familial multiple polyposis syndrome	2016-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001008195	SCV001167961	likely pathogenic	not provided	2018-05-25	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in APC is denoted c.1246dupT at the cDNA level and p.Tyr416LeufsX3 (Y416LfsX3) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CGCT[dupT]ACTG. The duplication causes a frameshift which changes a Tyrosine to a Leucine at codon 416, and creates a premature stop codon at position 3 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature as a germline variant, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on currently available evidence, we consider this duplication to be a likely pathogenic variant.