Submissions for variant NM_000038.6(APC):c.8068G>A (p.Ala2690Thr)

gnomAD frequency: 0.00146  dbSNP: rs140868933

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200966	SCV000149034	benign	not specified	2018-01-30	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122806	SCV000166063	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115125	SCV000183836	benign	Hereditary cancer-predisposing syndrome	2014-12-30	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000200966	SCV000538290	benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.5% (102/6614) Finnish; ClinVar: 3 B, 1 VUS
Color Diagnostics, LLC DBA Color Health	RCV000115125	SCV000681909	benign	Hereditary cancer-predisposing syndrome	2016-03-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000200966	SCV000805476	benign	not specified	2017-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000200966	SCV000888774	benign	not specified	2021-01-29	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000200966	SCV002069712	benign	not specified	2018-07-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115125	SCV002531526	benign	Hereditary cancer-predisposing syndrome	2020-03-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000200966	SCV002550668	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003326350	SCV004032621	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	APC: BP4, BS1
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115125	SCV005045389	benign	Hereditary cancer-predisposing syndrome	2024-05-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000122806	SCV005083714	benign	Familial adenomatous polyposis 1	2024-04-12	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Pathway Genomics	RCV000122806	SCV000207331	benign	Familial adenomatous polyposis 1	2014-11-06	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353775	SCV000591219	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Ala2690Thr variant was not identified in the literature. The variant was identified in dbSNP (rs140868933) as “with other allele”, ClinVar (classified as benign by Invitae, Ambry Genetics, GeneDx, Color and 4 other submitters and likely benign by True Health Diagnostics and 1 other submitter), LOVD 3.0 (observed 6x) and UMD-LSDB (observed 2x). The variant was identified in control databases in 663 of 282,646 chromosomes (3 homozygous) at a frequency of 0.002 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: Finnish in 354 of 25,120 chromosomes (freq: 0.01), Other in 18 of 7220 chromosomes (freq: 0.002), European in 264 of 128,976 chromosomes (freq: 0.002), South Asian in 19 of 30,616 chromosomes (freq: 0.0006), Latino in 6 of 35,434 chromosomes (freq: 0.0002), African in 2 of 24,962 chromosomes (freq: 0.00008), while the variant was not observed in the Ashkenazi Jewish, and East Asian populations. The p.Ala2690Thr residue is not conserved in mammals and four out of five 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
True Health Diagnostics	RCV000115125	SCV000805209	likely benign	Hereditary cancer-predisposing syndrome	2018-04-05	no assertion criteria provided	clinical testing