ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5363G>A (p.Arg1788His) (rs201472075)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000590729 SCV000109827 uncertain significance not provided 2013-03-12 criteria provided, single submitter clinical testing
GeneDx RCV000590729 SCV000209531 likely benign not provided 2021-05-20 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with endometrial cancer (Tian 2019); This variant is associated with the following publications: (PMID: 31054147, 23757202)
Ambry Genetics RCV000159559 SCV000216479 likely benign Hereditary cancer-predisposing syndrome 2020-08-24 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000232274 SCV000282779 likely benign Familial adenomatous polyposis 1 2020-11-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000393057 SCV000452025 uncertain significance APC-Associated Polyposis Disorders 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000211922 SCV000600113 uncertain significance not specified 2016-10-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000211922 SCV000694077 likely benign not specified 2021-01-16 criteria provided, single submitter clinical testing Variant summary: APC c.5363G>A (p.Arg1788His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 250160 control chromosomes, predominantly at a frequency of 0.00044 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 6 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 Latino origin. c.5363G>A has been reported in the literature in a study of individuals affected with endometrial cancer undergoing multigene panel testing (example, Tian_2019) and other settings of somatic tumor profiling (example, Koh_2017, Zehir_2019). 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Fulgent Genetics,Fulgent Genetics RCV000764566 SCV000895654 uncertain significance 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 Health, Inc RCV000159559 SCV000902937 likely benign Hereditary cancer-predisposing syndrome 2016-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000232274 SCV001550408 uncertain significance Familial adenomatous polyposis 1 no assertion criteria provided clinical testing The APC p.Arg1788His variant was not identified in the literature nor was it identified in GeneInsight-COGR, MutDB, UMD-LSDB, or Zhejiang University Database. The variant was identified in dbSNP (ID: rs201472075) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae and three other clinical laboratories), Cosmic (1x in prostate tissue), and in LOVD 3.0 databases. The variant was identified in control databases in 20 of 245188 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 15 of 33450 chromosomes (freq: 0.0005), European in 4 of 111090 chromosomes (freq: 0.00004), East Asian in 1 of 17178 chromosomes (freq: 0.00006), while the variant was not observed in the African, Other, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Arg1788 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance.
GenomeConnect - Invitae Patient Insights Network RCV000590729 SCV001749598 not provided not provided no assertion provided phenotyping only Variant interpreted as Likely benign and reported on 05-13-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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