Submissions for variant NM_000038.6(APC):c.1621C>T (p.Gln541Ter)

dbSNP: rs137854572

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000490845	SCV000579858	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-15	criteria provided, single submitter	clinical testing	The p.Q541* pathogenic mutation (also known as c.1621C>T), located in coding exon 12 of the APC gene, results from a C to T substitution at nucleotide position 1621. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This mutation has been reported in multiple individuals of various ethnicities diagnosed with familial adenomatous polyposis (FAP) (Miyoshi Y et al. Proc Natl Acad Sci U S A, 1992 May;89:4452-6; Fodde R et al. Genomics, 1992 Aug;13:1162-8; van der Luijt RB et al. Hum. Mutat., 1997;9:7-16; Wallis YL et al. J Med Genet, 1999 Jan;36:14-20; Resta N et al. Hum Mutat, 2001 May;17:434-5; De Rosa M et al. Hum Mutat, 2004 May;23:523-4; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Li N et al. J Gastroenterol Hepatol, 2019 Sep;34:1497-1503; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Invitae	RCV003743544	SCV000647187	pathogenic	Familial adenomatous polyposis 1	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln541*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (FAP) (PMID: 1316610, 1324223, 11317365, 20223039, 20685668). ClinVar contains an entry for this variant (Variation ID: 806). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657602	SCV000779343	pathogenic	not provided	2017-10-24	criteria provided, single submitter	clinical testing	This variant is denoted APC c.1621C>T at the cDNA level and p.Gln541Ter (Q541X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported several individuals with polyposis (Abraham 2000, De Rosa 2004, Fodde 1992, Friedl 2005, Miyoshi 1992, Resta 2001, Wallis 1999) and is considered pathogenic.
Eurofins Ntd Llc (ga)	RCV000657602	SCV000860241	pathogenic	not provided	2018-03-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002227968	SCV004044748	pathogenic	Familial adenomatous polyposis 1	2023-05-02	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.
OMIM	RCV000000843	SCV000020993	pathogenic	Familial adenomatous polyposis 1	1995-03-30	no assertion criteria provided	literature only
OMIM	RCV000000844	SCV000020994	pathogenic	Brain tumor-polyposis syndrome 2	1995-03-30	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000503851	SCV000591081	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Gln541X variant has been previously reported in the literature in at least 5 of 2936 proband chromsomes from individuals with familial adenomatous polyposis (Miyoshi 1992, Friedl 2005, Van der Luijt 2997, Fodde 1992, Wallis 1999). Furthermore, the variant was shown to segregate with disease in at least 4 affected family members increasing the likelihood this variant is pathogenic. This variant has also been reported in the HGMD, UMD, Cosmic, dbSNP (rs137854572), and LOVD databases. The p.Gln541X variant leads to a premature stop codon at position 541, 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 is classified as pathogenic.