Submissions for variant NM_000038.6(APC):c.5304G>A (p.Lys1768=)

gnomAD frequency: 0.00001  dbSNP: rs863224285

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004562403	SCV000252931	likely benign	Familial adenomatous polyposis 1	2024-11-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000570509	SCV000667346	likely benign	Hereditary cancer-predisposing syndrome	2015-09-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000608378	SCV000694073	likely benign	not specified	2019-08-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000608378	SCV000716616	likely benign	not specified	2017-03-03	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.
Color Diagnostics, LLC DBA Color Health	RCV000570509	SCV000906744	likely benign	Hereditary cancer-predisposing syndrome	2018-11-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000570509	SCV002535597	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003996942	SCV004838043	likely benign	Classic or attenuated familial adenomatous polyposis	2023-11-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004562403	SCV005082830	benign	Familial adenomatous polyposis 1	2024-04-01	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001357058	SCV005625378	uncertain significance	not provided	2024-09-30	criteria provided, single submitter	clinical testing	The APC c.5304G>A (p.Lys1768=) synonymous variant has not been reported in individuals with APC-related conditions in the published literature. The frequency of this variant in the general population, 0.000004 (1/250520 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect APC mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357058	SCV001552391	uncertain significance	not provided		no assertion criteria provided	clinical testing	The APC p.Lys1768= variant was not identified in the literature nor was it identified in the following databases: COGR, Cosmic, MutDB, LOVD 3.0, or the Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs863224285) “With Likely benign allele”, ClinVar (classified as likely benign by Invitae, Ambry Genetics and GeneDx, and uncertain significance by Laboratory Corporation of America), Clinvitae (2x), UMD-LSDB (1x as UV), and in control databases in 1 of 245394 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the European Non-Finnish population in 1 of 111050 chromosomes (freq: 0.000009), but not in African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Lys1768= variant is not expected to have clinical significance because it does not result in a change of amino acid and occurs outside of the splicing consensus sequence. However, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; however, this information is not predictive enough to assume pathogenicity. 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.