Submissions for variant NM_000038.6(APC):c.6526T>C (p.Leu2176=)

gnomAD frequency: 0.00023  dbSNP: rs183468041

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211925	SCV000209479	benign	not specified	2014-07-02	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	RCV000159522	SCV000213601	likely benign	Hereditary cancer-predisposing syndrome	2014-09-09	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.
Invitae	RCV003650404	SCV000252934	benign	Familial adenomatous polyposis 1	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000282259	SCV000452037	uncertain significance	APC-Associated Polyposis Disorders	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000211925	SCV000600130	benign	not specified	2017-07-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159522	SCV000681806	likely benign	Hereditary cancer-predisposing syndrome	2016-06-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587270	SCV000694098	benign	not provided	2016-05-09	criteria provided, single submitter	clinical testing	Variant summary: The APC c.6526T>C (p.Leu2176Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a damaging outcome for this variant. This variant was found in 24/119852 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.0005199 (6/11540). This frequency is about 9 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000602), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Clinical diagnostic laboratories classified this variant as Benign/Likely Benign. Taken together, this variant is classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000587270	SCV000805456	likely benign	not provided	2016-07-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587270	SCV001154475	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	APC: BP4, BP7
Sema4, Sema4	RCV000159522	SCV002528785	likely benign	Hereditary cancer-predisposing syndrome	2021-06-17	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211925	SCV002550645	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356057	SCV001551115	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Leu2176= variant was not identified in the literature nor was it identified in the GeneInsight, Cosmic, UMD and Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs183468041) “With unknown allele”, with a minor allele frequency of 0.0002 (1 of 5000 chromosomes in 1000 Genomes Project). In the NHLBI Exome Sequencing Project (Exome Variant Server), the variant was identified in 1 of 8590 European American chromosomes and was not found in 4390 African American chromosomes. In Exome Aggregation Consortium (ExAC) database, the variant was identified in 17 of 6605 European (Non-Finnish), 6 of 11540 Latinos and 1 of 9654 Africans, increasing the likelihood this could be a low frequency benign variant in certain populations of origin. The variant was identified in Clinvitae (1x as variant of unknown significance), LOVD (1x as no known pathogenicity) and InSiGHT Colon Cancer Database. In the ClinVar database the variant was reported as benign by GeneDX and as likely benign by Ambry Genetics. The p.Leu2176= 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000587270	SCV001809234	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587270	SCV001951870	likely benign	not provided		no assertion criteria provided	clinical testing