Submissions for variant NM_000038.6(APC):c.4360A>G (p.Lys1454Glu)

gnomAD frequency: 0.00271  dbSNP: rs111866410

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200964	SCV000149001	benign	not specified	2016-05-27	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000987572	SCV000153821	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115092	SCV000186657	benign	Hereditary cancer-predisposing syndrome	2015-01-20	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238996	SCV000297022	uncertain significance	Familial multiple polyposis syndrome	2015-10-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000264340	SCV000452011	likely benign	APC-Associated Polyposis Disorders	2016-06-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000200964	SCV000538293	likely benign	not specified	2016-08-12	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency high for disorder; multiple papers question pathogenicity
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586737	SCV000694052	likely benign	not provided	2016-09-16	criteria provided, single submitter	clinical testing	Variant summary: The APC c.4360A>G (p.Lys1454Glu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant is not located in any known domain/repeat (InterPro). This variant was found in 68/123380 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0053867 (56/10396). This frequency is about 75 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In literature, the variant has also been reported in patients of various cancer phenotypes (such as FAP, prostate cancer, hepatic cancer, CRC, bladder cancer and B-cell lymphoma) including somatic occurrences, however, without strong evidence for causality. One functional study showed that this variant has a normal effect in an in vitro beta-cateninregulated transcription (CRT) assay (Azzopardi_2008). Multiple clinical labs have classified this variant as benign/likely benign (3 labs) to uncertain significance (1 lab and 1 database). Taken together, this variant has currently been classified as a Likely Benign.
PreventionGenetics, part of Exact Sciences	RCV000200964	SCV000805408	benign	not specified	2017-06-09	criteria provided, single submitter	clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000200964	SCV000864337	likely benign	not specified	2017-09-05	criteria provided, single submitter	clinical testing	BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory).
Color Diagnostics, LLC DBA Color Health	RCV000115092	SCV000902616	benign	Hereditary cancer-predisposing syndrome	2016-03-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000987572	SCV001136911	benign	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000200964	SCV002047313	benign	not specified	2021-01-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000200964	SCV002069704	benign	not specified	2019-07-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115092	SCV002532048	benign	Hereditary cancer-predisposing syndrome	2020-11-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000200964	SCV004025062	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148365	SCV000190057	uncertain significance	Colorectal adenoma	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001270348	SCV001450573	likely benign	Familial colorectal cancer		no assertion criteria provided	clinical testing	The APC p.Lys1454Glu variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was identified in ClinVar (Conflicting interpretations of pathogencitiy. Benign(6);Likely benign(4);Uncertain significance(1) ) and Cosmic (Reported x5 Confirmed somatic, identified in tumor tissue from urinary tract (x3), prostate, and haematopoetic and lymphoid tissue) databases. The variant was identified in control databases in 228 of 282622 chromosomes at a frequency of 0.0008067 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 206 of 24960 chromosomes (freq: 0.008253), Latino in 16 of 35416 chromosomes (freq: 0.000452), Other in 3 of 7214 chromosomes (freq: 0.000416), European (Finnish) in 1 of 25120 chromosomes (freq: 0.00004), European (non-Finnish) in 2 of 128990 chromosomes (freq: 0.000016), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Lys1454 residue is conserved in mammals but not in more distantly related organisms, however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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. One functional study found that the p.Lys1454Glu variant suppresses beta-catenin mediated transcription at a level similar to wild-type APC in a cell culture assay, and is therefore predicted to have no effect on APC protein function (Azzopardi_2008_PMID:18199528). 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.