Submissions for variant NM_000038.6(APC):c.477C>G (p.Tyr159Ter)

dbSNP: rs863224281

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236674	SCV000293415	pathogenic	not provided	2022-05-17	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26414517, 8956059, 15951963, 20223039, 25525159, 23159591, 21779980)
Invitae	RCV003535655	SCV000768138	pathogenic	Familial adenomatous polyposis 1	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr159*) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). 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 premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 8956059, 15951963, 20223039). ClinVar contains an entry for this variant (Variation ID: 246084). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001023029	SCV001184844	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	The p.Y159* pathogenic mutation (also known as c.477C>G), located in coding exon 4 of the APC gene, results from a C to G substitution at nucleotide position 477. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. This mutation has been identified in multiple patients with classical familial adenomatous polyposis (FAP) and attenuated FAP (AFAP)(Friedl W and Aretz S. Hered Cancer in Clin Practice. 2005 Sep 15;3(3):95-114; Marshall B et al. Hum Mut. 1996; 8(4):395-396). A different nucleotide substitution at this position (c.477C>A) that results in the same stop codon has been seen in multiple patients with FAP, including a patient with the cribriform-morula variant of papillary thyroid carcinoma (Jarry J et al. Fam. Cancer. 2011 Dec;10(4):659-65; Uchino S et al. J. Clin. Endocrinol. Metab. 2016 Sep:jc20162043). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000236674	SCV001714740	pathogenic	not provided	2019-11-03	criteria provided, single submitter	clinical testing	PVS1, PM2, PP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844100	SCV002103378	pathogenic	Familial multiple polyposis syndrome	2022-02-10	criteria provided, single submitter	clinical testing	Variant summary: APC c.477C>G (p.Tyr159X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 278570 control chromosomes (gnomAD). c.477C>G has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (example: Marshall_1996, Friedl_2005, Truta_2005, Chang_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV002519826	SCV004044751	pathogenic	Familial adenomatous polyposis 1	2023-04-26	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.
Baylor Genetics	RCV002519826	SCV004198414	pathogenic	Familial adenomatous polyposis 1	2023-09-15	criteria provided, single submitter	clinical testing