ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3352A>G (p.Asn1118Asp) (rs140493115)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081816 SCV000166028 benign Familial adenomatous polyposis 1 2020-12-07 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: 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 Health, Inc RCV000129162 SCV000681593 likely benign Hereditary cancer-predisposing syndrome 2016-03-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 2018-04-10 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 Clinical Services Laboratory,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.
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.

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