ClinVar Miner

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

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Total submissions: 3
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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.

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