Submissions for variant NM_000038.6(APC):c.3006C>T (p.Ala1002=)

gnomAD frequency: 0.00020  dbSNP: rs72541810

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211905	SCV000209477	benign	not specified	2014-08-26	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.
Ambry Genetics	RCV000159520	SCV000213108	likely benign	Hereditary cancer-predisposing syndrome	2014-08-15	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	RCV000205109	SCV000260133	likely benign	Familial adenomatous polyposis 1	2024-01-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000858104	SCV000600072	benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159520	SCV000681570	likely benign	Hereditary cancer-predisposing syndrome	2016-05-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000205109	SCV000785986	likely benign	Familial adenomatous polyposis 1	2018-01-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000858104	SCV001154461	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	APC: BP4, BP7
Illumina Laboratory Services, Illumina	RCV001253906	SCV001429787	likely benign	APC-Associated Polyposis Disorders	2019-02-13	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000858104	SCV001473648	likely benign	not provided	2019-10-16	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000858104	SCV002010890	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000159520	SCV002529325	likely benign	Hereditary cancer-predisposing syndrome	2021-02-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211905	SCV002550608	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000205109	SCV004018510	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.
All of Us Research Program, National Institutes of Health	RCV003998399	SCV004839756	likely benign	Classic or attenuated familial adenomatous polyposis	2024-02-05	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000159520	SCV000787834	likely benign	Hereditary cancer-predisposing syndrome	2017-12-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356478	SCV001551659	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Ala1002= variant was not identified in the literature, but was identified in dbSNP (ID: rs72541810) as “Likely Benign”, ClinVar database (3 submissions: 1x Benign by GeneDx, 2x Likely Benign by Ambry Genetics & Invitae), COSMIC (Adenocarcinoma of the large intestine), LOVD Zhejiang Colon Cancer Database (LOVD) (unknown), Clinvitae database (as 2x Likely Benign and 1x Benign). This variant was also identified in the NHLBI GO Exome Sequencing Project in 3 of 8600 European American alleles (Freq: 0.00034) and the Exome Aggregation Consortium database (August 8th 2016) in 21 of 121266 chromosomes (freq. 0.000217) in the following populations: European (Non-Finnish) in 20 of 66618 chromosomes (freq. 0.0003), Latino in 1 of 11574 chromosomes (freq. 8.4 x 10 -5), but was not seen in African, East Asian, Finnish, other and South Asian populations. This variant was not identified in the InSiGHT Colon Cancer Gene Variant Database (LOVD), GeneInsight - COGR, UMD and the 1000 Genome Project database. In addition this variant was identified by our laboratory in a patient with MAP as co-occurring with pathogenic MUTYH homozygous variants (p.Tyr179Cys) increasing the likelihood that the p.Ala1002+ variant does not have clinical significance. The p.Ala1002= 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.