Submissions for variant NM_000038.6(APC):c.6873A>T (p.Gln2291His)

gnomAD frequency: 0.00012  dbSNP: rs148878262

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131637	SCV000186661	benign	Hereditary cancer-predisposing syndrome	2014-11-28	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	RCV000034419	SCV000209541	likely benign	not provided	2021-06-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22703879, 27443514, 28135145, 28873162, 27600092, 25479140)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168325	SCV000219012	likely benign	Familial adenomatous polyposis 1	2024-01-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000168325	SCV000488936	uncertain significance	Familial adenomatous polyposis 1	2016-07-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034419	SCV000600140	likely benign	not provided	2021-04-15	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211931	SCV000711422	uncertain significance	not specified	2016-12-28	criteria provided, single submitter	clinical testing	The p.Gln2291His variant in APC has been reported in 1 individual with atheroscl erosis (Johnston 2012), but has also been identified in 14/66516 European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs148878262). Computational prediction tools and conservation analysis su ggest that the p.Gln2291His variant may not impact the protein, though this info rmation is not predictive enough to rule out pathogenicity. This variant is list ed in ClinVar with multiple submitters classifying it as a variant of uncertain significance (ClinVar ID: 41534). In summary, the clinical significance of the p.Gln2291His variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV000131637	SCV000902692	likely benign	Hereditary cancer-predisposing syndrome	2016-03-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000168325	SCV001136939	uncertain significance	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001151804	SCV001312974	uncertain significance	APC-Associated Polyposis Disorders	2018-01-12	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211931	SCV001361370	likely benign	not specified	2024-01-15	criteria provided, single submitter	clinical testing	Variant summary: APC c.6873A>T (p.Gln2291His) results in a non-conservative amino acid change located in the basic domain (IPR009234) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 250976 control chromosomes, predominantly at a frequency of 0.00031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.6873A>T has been reported in the literature in individuals affected with colorectal cancer (e.g. Yurgelun_2017), endometrial cancer (e.g. Ring_2016), pancreatic cancer (e.g. Grant_2015), and atherosclerosis (no information regarding cancer history, Johnson_2012). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22703879, 25722345, 25479140, 27443514, 28135145). ClinVar contains an entry for this variant (Variation ID: 41534). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000131637	SCV002526786	likely benign	Hereditary cancer-predisposing syndrome	2022-01-30	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211931	SCV002760364	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000168325	SCV004018797	uncertain significance	Familial adenomatous polyposis 1	2023-02-22	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV003996165	SCV004843472	likely benign	Classic or attenuated familial adenomatous polyposis	2024-01-11	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034419	SCV000043136	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353490	SCV000591204	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Gln2291His variant was not identified in the literature nor was it identified in COSMIC, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database and UMD. The variant was identified in dbSNP (ID: rs148878262) “With other allele”, Clinvar database (with conflicting interpretations of pathogenicity, classified as benign by Ambry Genetics and uncertain significance by GeneDx, Invitae and Biesecker Laboratory-ClinSeq Project), and the Clinvitae database. This variant was also identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004), HAPMAP-EUR in 2 of 1006 chromosomes (frequency: 0.002), NHLBI GO Exome Sequencing Project (ESP) in 6 of 8600 European American alleles, and the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 14 of 66516 chromosomes (frequency:0.0002)in the European (Non-Finnish) population. The p.Gln2291 residue is not conserved across mammals and the variant amino acid His is present in rat and hedgehog. 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 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.
True Health Diagnostics	RCV000131637	SCV000787838	likely benign	Hereditary cancer-predisposing syndrome	2017-12-01	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000034419	SCV001740191	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000034419	SCV001807264	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000034419	SCV001922700	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000034419	SCV001951986	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739318	SCV005366991	uncertain significance	APC-related disorder	2024-06-21	no assertion criteria provided	clinical testing	The APC c.6873A>T variant is predicted to result in the amino acid substitution p.Gln2291His. This variant was identified among study participants with colorectal cancer but was classified as a variant of uncertain significance (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145). This variant was also identified in an individual with pancreatic cancer and in an individual with endometrial cancer and was classified as a variant of uncertain significance (Supplementary table 1, Grant et al. 2015. PubMed ID: 25479140; Table S2, Ring et al. 2016. PubMed ID: 27443514). This variant was also identified in an individual with colorectal, ovarian and uterine cancer (Bhai P et al. 2021. PubMed ID: 34326862). This variant was detected in an individual with a range of atherosclerosis phenotypes, and no personal and/or family history of cancer (Table S1, Johnston et al. 2012. PubMed ID: 22703879). In ClinVar, this variant has conflicting interpretations regarding its pathogenicity ranging from benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/41534/). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD which is at a higher frequency then expected for pathogenic variants in this gene. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.