ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4765C>T (p.Arg1589Cys)

dbSNP: rs72541813
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002228999 SCV000218545 likely benign Familial adenomatous polyposis 1 2021-09-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508130 SCV000600104 uncertain significance not specified 2017-03-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565123 SCV000667448 likely benign Hereditary cancer-predisposing syndrome 2020-02-13 criteria provided, single submitter clinical testing In silico models in agreement (benign);No disease association in small case-control study;Other data supporting benign classification
Color Diagnostics, LLC DBA Color Health RCV000565123 SCV000681684 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-16 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 1589 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been reported in a healthy control individual (PMID: 18199528). This variant has also been identified in 23/282472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000508130 SCV001748759 likely benign not specified 2021-06-21 criteria provided, single submitter clinical testing Variant summary: APC c.4765C>T (p.Arg1589Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251116 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), suggesting that the variant is a benign polymorphism. In a case-control study, the variant was absent in 691 unrelated North American patients with colorectal adenomas, but was found in 969 matched healthy controls (Azzopardi_2008). In addition, the variant, c.4765C>T, has been reported in the literature as a germline variant in an individual affected with melanocytic nevi (Pawlikowski_2015), and was found in a suspected premalignant pancreatic lesion and in tumor samples (melanoma, gastric carcinoma), however it was unclear if it occurred as a germline or somatic alteration (Garman_2017, Plougmann_2020, Sa_2020). These reports do 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=2) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx RCV001589045 SCV001826522 uncertain significance not provided 2019-06-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 18199528, 25815427)
Genetic Services Laboratory,University of Chicago RCV000508130 SCV002070429 uncertain significance not specified 2021-12-22 criteria provided, single submitter clinical testing DNA sequence analysis of the APC gene demonstrated a sequence change, c.4765C>T, in exon 16 that results in an amino acid change, p.Arg1589Cys. This sequence change has been described in the gnomAD database with a frequency of 0.01%in the African/African American subpopulation (dbSNP rs72541813). The p.Arg1589Cys change affects a moderately conserved amino acid residue located in a domain of the APC protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1589Cys substitution. This sequence change does not appear to have been previously described in individuals with APC-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg1589Cys change remains unknown at this time.

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