Submissions for variant NM_000038.6(APC):c.120G>A (p.Glu40=)

gnomAD frequency: 0.00161  dbSNP: rs142720069

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082954	SCV000166013	benign	Familial adenomatous polyposis 1	2025-02-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000201994	SCV000167017	benign	not specified	2014-04-07	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	RCV000123674	SCV000213029	likely benign	Hereditary cancer-predisposing syndrome	2014-09-18	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.
Illumina Laboratory Services, Illumina	RCV000340295	SCV000451981	benign	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000123674	SCV000681447	benign	Hereditary cancer-predisposing syndrome	2016-03-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589882	SCV000693988	benign	not provided	2016-05-02	criteria provided, single submitter	clinical testing	Variant summary: The APC c.120G>A variant affects a conserved nucleotide, resulting in synonymous amino acid change. This variant is found in 81/121234 control chromosomes at a frequency of 0.0006681, which is about 11 times greater than the estimated maximal expected frequency of a pathogenic allele (0.0000602) in this gene, suggesting this variant is benign. In addition, multiple clinical laboratories have classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories. Taken together, this variant has been classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000201994	SCV000805364	benign	not specified	2017-12-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589882	SCV000887501	benign	not provided	2022-08-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589882	SCV001477712	likely benign	not provided	2023-05-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000123674	SCV002538448	benign	Hereditary cancer-predisposing syndrome	2021-01-26	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000589882	SCV003916964	likely benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	APC: BP4, BS1
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001082954	SCV004015770	benign	Familial adenomatous polyposis 1	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001082954	SCV004931019	benign	Familial adenomatous polyposis 1	2024-02-22	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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000123674	SCV005045414	benign	Hereditary cancer-predisposing syndrome	2024-02-20	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000589882	SCV005221600	likely benign	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV000201994	SCV000256909	likely benign	not specified		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001082954	SCV001550237	likely benign	Familial adenomatous polyposis 1		no assertion criteria provided	clinical testing	The APC p.Glu40= variant was identified in 4 of 3182 proband chromosomes (frequency: 0.0013) from individuals or families with FAP (Kerr 2013). The variant was also identified in dbSNP (ID: rs142720069) as "With other allele ", and in ClinVar database (classified as benign by Invitae, GeneDx, Color Genimics and two clinical laboratories; as likely benign by Ambry Genetics and three clinical laboratories). The variant was not identified in GeneInsight-COGR, Cosmic, LOVD 3.0, UMD-LSDB, or Zhejiang University, databases. The variant was identified in control databases in 194 of 276970 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 128 of 24032 chromosomes (freq: 0.005), Other in 3 of 6454 chromosomes (freq: 0.0005), Latino in 19 of 34412 chromosomes (freq: 0.0006), European in 2 of 126492 chromosomes (freq: 0.00002), Ashkenazi Jewish in 42 of 10150 chromosomes (freq: 0.004), while the variant was not observed in the East Asian, Finnish, and South Asian populations. The p.Glu40= 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 occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.