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

dbSNP: rs72541813

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003650441	SCV000218545	likely benign	Familial adenomatous polyposis 1	2024-01-27	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	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 Diagnostics, LLC DBA Color Health	RCV000565123	SCV000681684	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-20	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). 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	2023-10-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18199528, 26178707, 31552911, 32070411, 35534218, 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.