Submissions for variant NM_000038.6(APC):c.5017G>A (p.Glu1673Lys)

gnomAD frequency: 0.00001  dbSNP: rs587779796

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000758730	SCV000149008	uncertain significance	not provided	2022-04-08	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); 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 breast and/or ovarian cancer (Cock-Rada 2018); This variant is associated with the following publications: (PMID: 25257991, 25925381, 18199528, 28528518)
Ambry Genetics	RCV000219975	SCV000277295	likely benign	Hereditary cancer-predisposing syndrome	2020-08-07	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.
Counsyl	RCV000410427	SCV000487964	uncertain significance	Familial adenomatous polyposis 1	2015-12-18	criteria provided, single submitter	clinical testing
Invitae	RCV000410427	SCV000552695	benign	Familial adenomatous polyposis 1	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000219975	SCV000681699	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1673 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 reported for this variant. This variant has not been reported in individuals affected with APC-related disorders. This variant has been identified in 6/250204 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.
Mendelics	RCV003492449	SCV000838126	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758730	SCV000887529	uncertain significance	not provided	2021-05-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000219975	SCV002534965	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-05	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410427	SCV004018803	uncertain significance	Familial adenomatous polyposis 1	2023-02-22	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences	RCV003952545	SCV004774683	uncertain significance	APC-related condition	2024-01-29	criteria provided, single submitter	clinical testing	The APC c.5017G>A variant is predicted to result in the amino acid substitution p.Glu1673Lys. This variant has been reported as a germline alteration in a patient with hereditary breast and/or ovarian cancer (as a variant of uncertain significance), and has also been documented in a tumor sample from a patient with peripheral T-cell lymphoma (Cock-Rada et al. 2018. PubMed ID: 28528518; Schatz et al. 2014. PubMed ID: 25257991). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain, likely benign or benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127301/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355446	SCV001550332	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Glu1673Lys variant was identified in 2 of 226 proband chromosomes (frequency: 0.009) from individuals or families with breast cancer, ovarian cancer or T-cell lymphoma (Cock-Rada 2018, Schatz 2015). The variant was also identified in dbSNP (ID: rs587779796 as "With Pathogenic, Uncertain significance allele") and ClinVar (5x as uncertain significance by GeneDx, Ambry Genetics, Counsyl, Invitae, and Color Genomics). The variant was not identified in the COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, or Zhejiang University database. The variant was identified in control databases in 6 of 244982 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 3 of 33530 chromosomes (freq: 0.00009), European in 3 of 110694 chromosomes (freq: 0.00003); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Glu1673 residue is not conserved in mammals and 4 of 5 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.