ClinVar Miner

Submissions for variant NM_000038.6(APC):c.777G>T (p.Arg259=) (rs147704593)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079901 SCV000166061 benign Familial adenomatous polyposis 1 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000211894 SCV000167021 benign not specified 2014-02-20 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000123678 SCV000213055 likely benign Hereditary cancer-predisposing syndrome 2014-09-25 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Health, Inc RCV000123678 SCV000537449 likely benign Hereditary cancer-predisposing syndrome 2016-06-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759445 SCV000888768 benign not provided 2018-04-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000211894 SCV000916471 benign not specified 2018-04-16 criteria provided, single submitter clinical testing Variant summary: APC c.777G>T alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 77 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. The variant, c.777G>T, has been reported in the literature in one individual affected with Familial Adenomatous Polyposis (Kerr 2013). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001151508 SCV001312639 uncertain significance APC-Associated Polyposis Disorders 2017-05-19 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000759445 SCV001335133 likely benign not provided 2021-06-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353450 SCV000591052 likely benign Carcinoma of colon no assertion criteria provided clinical testing The APC p.Arg259= variant was identified in 1 of 3182 proband chromosomes (frequency: 0.0003) from individuals or families with FAP (Kerr 2013). The variant was also identified in dbSNP (ID: rs147704593) as With other allele, ClinVar (classified as benign by Invitae, GeneDx; classified as likely benign by Ambry Genetics, Color Genomics and two clinical laboratories), GeneInsight-COGR, and LOVD 3.0 databases. The variant was not identified in UMD-LSDB database or Zhejiang Colon Cancer Database. The variant was identified in control databases in 65 of 245844 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 4 of 5476 chromosomes (freq: 0.000731), Latino in 1 of 33516 chromosomes (freq: 0.00003), European Non-Finnish in 6 of 111470 chromosomes (freq: 0.000054), Ashkenazi Jewish in 54 of 9836 chromosomes (freq: 0.00549), while the variant was not observed in the African, East Asian, European Finnish, and South Asian populations. The p.Arg259= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000211894 SCV000691709 likely benign not specified no assertion criteria provided clinical testing

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