ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1866C>A (p.Tyr622Ter) (rs876658355)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217597 SCV000278448 pathogenic Hereditary cancer-predisposing syndrome 2019-02-11 criteria provided, single submitter clinical testing The p.Y622* pathogenic mutation (also known as c.1866C>A), located in coding exon 14 of the APC gene, results from a C to A substitution at nucleotide position 1866. This changes the amino acid from a tyrosine to a stop codon within coding exon 14. This mutation has been reported in multiple unrelated families diagnosed with familial adenomatous polyposis (FAP) (Miyoshi Y et al. Proc. Natl. Acad. Sci. U.S.A. 1992 May;89:4452-6; Miyaki M et al. Cancer Res. 1994 Jun;54:3011-20; van der Luijt RB et al. Hum. Mutat. 1997;9:7-16). In one study, this mutation was observed to segregate with disease in a familial FAP kindred (Olschwang S et al. Am. J. Hum. Genet. 1993 Feb;52:273-9). In addition to the clinical data presented in the literature, 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000584117 SCV000883405 pathogenic not provided 2018-02-15 criteria provided, single submitter clinical testing The APC c.1866C>A; p.Tyr622Ter variant (rs876658355) has been observed in individuals and families affected with familial adenomatous polyposis (FAP) ( Miyaki 1994, Miyoshi 1992, Olschwang 1993, van der Luijt 1997). This variant is reported as pathogenic in ClinVar (Variation ID: 233973) and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1866C>G; p.Tyr622Ter) has been reported in individuals with FAP and is considered pathogenic (Friedl 2005). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the above information, this variant is considered pathogenic. References: Friedl W et al. Familial Adenomatous Polyposis: Experience from a Study of 1164 Unrelated German Polyposis Patients. Hered Cancer Clin Pract. 2005; 3(3): 95–114. Miyaki M et al. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res. 1994 Jun 1;54(11):3011-20. Miyoshi Y et al. Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4452-6. Olschwang S et al. Germ-line mutations in the first 14 exons of the adenomatous polyposis coli (APC) gene. Am J Hum Genet. 1993 Feb;52(2):273-9. van der Luijt R et al. Molecular analysis of the APC gene in 105 Dutch kindreds with familial adenomatous polyposis: 67 germline mutations identified by DGGE, PTT, and southern analysis. Hum Mutat. 1997;9(1):7-16.
Invitae RCV000816919 SCV000957448 pathogenic Familial adenomatous polyposis 1 2018-09-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr622*) in the APC gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with familial adenomatous polyposis (PMID: 1316610, 8187091, 20685668, 8990002, 8381580). ClinVar contains an entry for this variant (Variation ID: 233973). Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000504287 SCV000591093 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The APC p.Tyr622X variant was identified in 5 of 906 proband chromosomes (frequency: 0.006) from individuals or families with Familial adenomatous polyposis (FAP) (Miyoshi_1992_1316610, van der Luijt_1997_8990002, Olschwang_1993_8381580, Enomoto_2000_10768871, Miyaki_1994_8187091). The variant was also identified in HGMD,“InSiGHT Colon Cancer Database, and UMD (11X as an unvalidated variant). The p.Tyr622X variant leads to a premature stop codon at position 622, 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 familial adenomatous polyposis 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000584117 SCV000691719 likely pathogenic not provided no assertion criteria provided clinical testing

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