Submissions for variant NM_000038.6(APC):c.2205G>A (p.Ala735=)

gnomAD frequency: 0.00019  dbSNP: rs141001261

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162793	SCV000213271	likely benign	Hereditary cancer-predisposing syndrome	2014-12-19	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199939	SCV000252908	likely benign	Familial adenomatous polyposis 1	2025-01-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000199939	SCV000488961	likely benign	Familial adenomatous polyposis 1	2016-07-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000429527	SCV000512067	benign	not specified	2015-03-20	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	RCV000162793	SCV000681507	likely benign	Hereditary cancer-predisposing syndrome	2016-05-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587002	SCV000694009	benign	not provided	2016-06-10	criteria provided, single submitter	clinical testing	Variant summary: The APC c.2205G>A (p.Ala735Ala) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 in silico prediction tools predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. This variant was observed in the large, broad control population, ExAC, with an allele frequency of 16/120502 (1/7530), predominantly observed in the African subpopulation, 5/10246 (1/2049), which exceeds the estimated maximal expected allele frequency for a pathogenic APC variant of 1/14005 (0.0000714). Therefore, suggesting this is likely a benign polymorphism found primarily in population(s)of African origin. In addition, multiple clinical diagnostic laboratories and a publication classified this variant as Likely Benign. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000429527	SCV000887508	benign	not specified	2022-01-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001155353	SCV001316777	uncertain significance	APC-Associated Polyposis Disorders	2018-07-10	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sema4, Sema4	RCV000162793	SCV002535923	likely benign	Hereditary cancer-predisposing syndrome	2021-11-04	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000199939	SCV004018587	benign	Familial adenomatous polyposis 1	2023-02-17	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000429527	SCV004243232	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353912	SCV000591109	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Ala735Ala variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant was not identified in the literature, but was identified in dbSNP (ID: rs141001261) and in the COSMIC database. The variant is listed in the NHLBI Exome Sequencing Project with frequencies of 0.0001 in European American alleles and 0.0002 in African American alleles, though these frequencies are based solely on one occurrence of the variant allele in each cohort. 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 predicted benign.