ClinVar Miner

Submissions for variant NM_000038.6(APC):c.994C>T (p.Arg332Ter)

dbSNP: rs775126020
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164280 SCV000214907 pathogenic Hereditary cancer-predisposing syndrome 2022-03-30 criteria provided, single submitter clinical testing The p.R332* pathogenic mutation (also known as c.994C>T), located in coding exon 9 of the APC gene, results from a C to T substitution at nucleotide position 994. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been identified in many patients diagnosed with FAP or AFAP from various ethnicities (Soravia et al. Am J Hum Genet. 1998. 62:1290-1301; Gomez-Fernandez N et al. BMC Med Genet. 2009 Jun 16;10:57; Friedl W & Aretz S. Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114; Chubb D et al. J. Clin. Oncol. 2015 Feb;33(5):426-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
GeneDx RCV000202243 SCV000292448 pathogenic not provided 2021-10-26 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 (Lek et al., 2016); Observed in individuals with APC-related phenotypes (Soravia 1998, Andreutti-Zaugg 1999, Hutter 2001, Friedl 2005, Sieber 2006, Chubb 2015); This variant is associated with the following publications: (PMID: 28010732, 30072583, 16461775, 1646175, 11001924, 20223039, 20924072, 16134147, 17411426, 11748858, 19531215, 23159591, 25559809, 22987206, 11317365, 11960572, 19793053, 22425061, 20105204, 25525159, 9585611, 28790112, 29691710, 10094557, 31461190, 33468868, 33294277)
Color Diagnostics, LLC DBA Color Health RCV000164280 SCV000537665 pathogenic Hereditary cancer-predisposing syndrome 2023-12-11 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 10 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with familial adenomatous polyposis, attenuated familial adenomatous polyposis, and colorectal cancer (PMID: 9585611, 10713886, 11001924, 11748858, 11317365, 16461775, 17411426, 19531215, 20223039, 23159591, 25590978). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Invitae RCV002228714 SCV000552518 pathogenic Familial adenomatous polyposis 1 2024-01-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg332*) 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) and attenuated familial adenomatous polyposis (AFAP) (PMID: 9585611, 11748858, 17411426, 19531215, 25559809). ClinVar contains an entry for this variant (Variation ID: 184937). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202243 SCV000887559 pathogenic not provided 2022-12-22 criteria provided, single submitter clinical testing This nonsense variant causes the premature termination of APC protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with familial adenomatous polyposis (FAP) (PMIDs: 19531215 (2009), 11748858 (2001), 10713886 (2000)), suspected FAP (PMID: 20223039 (2005)), attenuated FAP (PMIDs: 17411426 (2007), 9585611 (1998)), colorectal cancer (PMID: 25559809 (2015)), and Lynch-like syndrome (PMID: 33294277 (2020)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000503333 SCV000916472 pathogenic Familial multiple polyposis syndrome 2018-04-18 criteria provided, single submitter clinical testing Variant summary: APC c.994C>T (p.Arg332X) 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. The variant was absent in 276792 control chromosomes (gnomAD). The variant, c.994C>T, has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (Cao_2000, Friedl_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000460182 SCV001499601 pathogenic Familial adenomatous polyposis 1 2020-04-02 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000202243 SCV002062608 pathogenic not provided 2021-11-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002498813 SCV002812650 pathogenic Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach 2022-01-04 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV002228714 SCV004044662 pathogenic Familial adenomatous polyposis 1 2023-04-28 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000202243 SCV000257040 pathogenic not provided no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000202243 SCV000591061 pathogenic not provided no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000202243 SCV002818448 not provided not provided no assertion provided phenotyping only Variant classified as Pathogenic and reported on 10-29-2021 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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