ClinVar Miner

Submissions for variant NM_000038.6(APC):c.70C>T (p.Arg24Ter) (rs145945630)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164002 SCV000214605 pathogenic Hereditary cancer-predisposing syndrome 2018-04-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000227124 SCV000282812 pathogenic Familial adenomatous polyposis 1 2018-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg24*) in the APC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs145945630, ExAC 0.03%). This variant has been reported in the literature in an individual affected with attenuated familial adenomatous polyposis (FAP) (PMID: 18433509), as well as an individual with suspected Lynch syndrome (PMID: 25980754). Deleterious variants in the 5' end of the APC gene have been shown to be associated with an attenuated phenotype of FAP, since alternative translational initiation at codon 184 may result in a partially functional APC protein (PMID: 12034871, 16461775, 18433509). However, this has not been experimentally tested for this particular variant. In the literature, exon 2 is also referred to as exon 1 (PMID: 18433509). ClinVar contains an entry for this variant (Variation ID: 184702). Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000227124 SCV000488376 likely pathogenic Familial adenomatous polyposis 1 2016-03-10 criteria provided, single submitter clinical testing
GeneDx RCV000482864 SCV000568259 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing This variant is denoted APC c.70C>T at the cDNA level and p.Arg24Ter (R24X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Yurgelun et al. (2015) reported this variant in an individual with a Lynch syndrome-associated cancer and/or colon polyps while Kanter-Smoler et al. (2008) reported this variant in an individual with an attenuated polyposis phenotype. It is considered pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000499913 SCV000591013 pathogenic Familial adenomatous polyposis 2014-04-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508297 SCV000602530 pathogenic not specified 2017-01-12 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844605 SCV000731596 pathogenic Familial multiple polyposis syndrome 2017-04-18 criteria provided, single submitter clinical testing The p.Arg24X variant in APC has been reported in 1 individual with attenuated FA P (AFAP) and 1 individual with suspected Lynch syndrome (Kanter-Smoler 2008, Yur gelun 2015) and has also been reported by other clinical laboratories in ClinVar (Variant ID 184702). It has been identified in 4/25788 Finnish chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs145945630). Please note that for diseases with clinical variability, reduced p enetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. This nonsense variant leads to a premature termination codon at position 24, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the APC gene is an established disease mechanism in individuals with FAP. However, truncating variants in the 5 ' end of the APC gene have typically been associated with AFAP (Jasperson 2017). In summary, this variant meets criteria to be classified as pathogenic for fami lial adenomatous polyposis, likely in the attenuated form, in an autosomal domin ant manner, based upon predicted impact to the protein, presence in affected ind ividuals, and low frequency in the general population. ACMG/AMP Criteria applie d: PVS1, PM2_supporting, PS4_Moderate (Richards 2015).
Fulgent Genetics,Fulgent Genetics RCV000763534 SCV000894347 pathogenic Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000164002 SCV000905870 pathogenic Hereditary cancer-predisposing syndrome 2016-05-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000499913 SCV000918469 pathogenic Familial adenomatous polyposis 2018-11-20 criteria provided, single submitter clinical testing Variant summary: APC c.70C>T (p.Arg24X) 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. Some truncating mutations in the 5' end of the APC gene have been found to be associated with an attenuated phenotype of familial adenomatous polyposis coli (AFAP), as it was demonstrated that a downstream in-frame alternative start codon (codon 184) may generate a partially functional protein (see e.g. PMID: 12034871). However, to our knowledge, no experimental evidence demonstrating this scenario has been reported for the variant of interest. The variant allele was found at a frequency of 1.8e-05 in 276948 control chromosomes (gnomAD). c.70C>T has been reported in the literature in an individual affected with AFAP (Kanter-Smoler 2008) and in an other individual affected with Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). These data indicate that the variant may be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (5x)/likely pathogenic(1x). Based on the evidence outlined above, the variant was classified as pathogenic.

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