Submissions for variant NM_000038.6(APC):c.3352A>G (p.Asn1118Asp)

gnomAD frequency: 0.00021  dbSNP: rs140493115

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004566797	SCV000166028	benign	Familial adenomatous polyposis 1	2025-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129162	SCV000183894	benign	Hereditary cancer-predisposing syndrome	2014-12-09	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
GeneDx	RCV000034411	SCV000209513	likely benign	not provided	2020-09-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22703879, 25203624, 1338764, 15161437, 27621404, 28135145, 25231023, 15122587, 25148578, 27978560, 26373296, 22875147, 21859464, 25925381)
Color Diagnostics, LLC DBA Color Health	RCV000129162	SCV000681593	likely benign	Hereditary cancer-predisposing syndrome	2016-03-18	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000200963	SCV000862006	likely benign	not specified	2018-06-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034411	SCV000887521	benign	not provided	2022-09-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200963	SCV000916477	benign	not specified	2017-10-06	criteria provided, single submitter	clinical testing	Variant summary: The APC c.3352A>G (p.Asn1118Asp) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 110/278362 control chromosomes, predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.009593 (97/10112). This frequency is about 134 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. This variant has been reported in multiple affected individuals and two families with evidence of lack of co-segregation of variant with disease (Nagase_1992 and Zhou_2004). Moreover, one colon cancer patient also carried a pathogenic BRCA2 variant c.5946del/p.S1982RfsX22 (Pearlman_2016), further supporting the benign nature of this variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign; one other lab classified it as VUS, all without evidence for independent evaluation. Taken together, especially considering the high MAF in controls, evidence of lack of co-segregation of variant with disease, and co-occurrence with another pathogenic variant, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001253954	SCV001429838	likely benign	APC-Associated Polyposis Disorders	2017-04-27	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Sema4, Sema4	RCV000129162	SCV002533281	benign	Hereditary cancer-predisposing syndrome	2020-07-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000200963	SCV002550613	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129162	SCV004228166	likely benign	Hereditary cancer-predisposing syndrome	2023-10-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034411	SCV004701741	benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	APC: BS1, BS2
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034411	SCV000043120	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000200963	SCV000691734	uncertain significance	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000129162	SCV000693476	likely benign	Hereditary cancer-predisposing syndrome	2017-09-28	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000200963	SCV001550665	benign	not specified		no assertion criteria provided	clinical testing	The APC p.Asn1118Asp variant was identified in 5 of 1626 proband chromosomes (frequency: 0.003) from individuals or families with FAP, CRC, or atherosclerosis and was not identified in 384 control chromosomes from healthy individuals (Nagase 1992, Zhou 2004, Johnston 2012). The variant was also identified in dbSNP (ID: rs140493115) as "With other allele", in ClinVar (classified as benign by Invitae, Ambry Genetics, and Quest Diagnostics; as likely benign by GeneDx, Color Genomics, EGL, and True Health Diagnostics; as uncertain significance by Mayo Clinic and Biesecker Lab), LOVD 3.0 (classified as likely benign by one submitter and uncertain significance by one submitter). The variant was also identified by our laboratory in 1 individual with colon cancer. The variant was identified in control databases in 110 of 276246 chromosomes at a frequency of 0.0004 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: Other in 3 of 6454 chromosomes (freq: 0.0005), Latino in 1 of 34378 chromosomes (freq: 0.00003), European Non-Finnish in 9 of 126002 chromosomes (freq: 0.00007), Ashkenazi Jewish in 97 of 10112 chromosomes (freq: 0.0096); it was not observed in the African, East Asian, Finnish, and South Asian populations. The p.Asn1118 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The variant was also identified in a patient with CRC and a very strong family history of CRC as well as breast-ovarian cancer where it did not co-segregate with disease, specifically 2 members with colon cancer tested negative for the variant (Zhou 2004). In addition the variant was described to not segregate well with the disease phenotype in a family with FAP and a co-occurring pathogenic APC variant (Nagase 1992). The variant has also been identified in an individual with colorectal cancer co-occurring with a pathogenic variant (BRCA2, c.5946del, p.S1982Rfs*22; Pearlman 2017). In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003924891	SCV004743345	likely benign	APC-related disorder	2019-05-17	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).