Submissions for variant NM_000038.6(APC):c.3436C>T (p.Arg1146Cys)

gnomAD frequency: 0.00004  dbSNP: rs202168805

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003534468	SCV000254008	uncertain significance	Familial adenomatous polyposis 1	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1146 of the APC protein (p.Arg1146Cys). This variant is present in population databases (rs202168805, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer and/or endometrial carcinoma (PMID: 27443514, 31360874). ClinVar contains an entry for this variant (Variation ID: 216162). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000236811	SCV000292456	uncertain significance	not provided	2017-09-04	criteria provided, single submitter	clinical testing	This variant is denoted APC c.3436C>T at the cDNA level, p.Arg1146Cys (R1146C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant was identified in the germline of an individual with endometrial cancer, and in a breast cancer tumor, germline status unknown (Ring 2016, Wen 2015). APC Arg1146Cys was observed at an allele frequency of 0.018% (3/16462) in individuals of South Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Arg1146Cys occurs at a position that is conserved across species and is located in the beta-catenin binding domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Arg1146Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000491194	SCV000579813	likely benign	Hereditary cancer-predisposing syndrome	2021-05-26	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	RCV000491194	SCV000681601	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1146 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in a cohort of individuals affected with early onset colorectal cancer (PMID: 31360874), an individual affected with endometrial cancer (PMID: 27443514), and an individual affected with breast cancer, although this individual also carries a truncating TP53 variant (PMID: 26320869). This variant has been identified in 14/282312 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236811	SCV000887522	uncertain significance	not provided	2019-12-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553560	SCV001774453	uncertain significance	not specified	2021-07-26	criteria provided, single submitter	clinical testing	Variant summary: APC c.3436C>T (p.Arg1146Cys) 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 5.2e-05 in 250924 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (5.2e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.3436C>T has been reported in the literature as a VUS in settings of multigene panel in one individual from a cohort of patients with endometrial carcinoma (example, Ring_2016) and WES in a cohort of young onset colorectal cancers (example, Toh_2018). These report(s) 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. Five 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 uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000236811	SCV002011092	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000491194	SCV002535527	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-15	criteria provided, single submitter	curation