Submissions for variant NM_000038.6(APC):c.6821C>T (p.Ala2274Val)

gnomAD frequency: 0.00088  dbSNP: rs34919187

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000034396	SCV000149024	likely benign	not provided	2021-06-22	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22703879, 21859464, 25203624, 27600092, 28202063, 28125075, 18199528, 25637381, 26332594, 27060149, 28283864, 27621404, 25637981)
Invitae	RCV003743547	SCV000153837	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115115	SCV000172878	likely benign	Hereditary cancer-predisposing syndrome	2018-07-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
CSER _CC_NCGL, University of Washington	RCV000590867	SCV000190053	likely benign	Familial multiple polyposis syndrome	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 53 year old male with a history of ~10 colon polyps and colon cancer diagnosed at age 53. Family history of colon polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
PreventionGenetics, part of Exact Sciences	RCV000247116	SCV000301604	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000343531	SCV000452041	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034396	SCV000602526	likely benign	not provided	2018-06-04	criteria provided, single submitter	clinical testing	The APC c.6821C>T; p.Ala2274Val variant (rs34919187), is reported in patients with colorectal carcinomas (Azzopardi 2008), but is also found in the general population at a frequency greater than expected for the disorder (Amendola 2015, Olfson 2015). This variant is reported as benign or likely benign by several laboratories in ClinVar (Variation ID: 41511), and found in the general population with an overall allele frequency of 0.1% (295/276782 alleles) in the Genome Aggregation Database. The alanine at codon 2274 is weakly conserved, and computational analyses (SIFT, MutationTaster, Align GVGD) predict that this variant is tolerated. Furthermore, this is a missense variant and the vast majority of pathogenic APC variants are truncating nonsense or frameshift variants (see InSiGHt, Kerr 2013). Based on available information, this variant is considered to be likely benign. REFERENCES Link to InSiGHt: https://www.insight-group.org/syndromes/adenomatous-polyposis/. Amendola LM et al. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res. 2015 Mar;25(3):305-15. Azzopardi D et al. Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas. Cancer Res. 2008 Jan 15;68(2):358-63. Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31-43. Olfson E et al. Identification of Medically Actionable Secondary Findings in the 1000 Genomes. PLoS One. 2015 Sep 2;10(9):e0135193.
Counsyl	RCV000119123	SCV000786193	likely benign	Familial adenomatous polyposis 1	2018-03-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000119123	SCV000838143	likely benign	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034396	SCV000887545	benign	not provided	2022-10-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115115	SCV000902580	benign	Hereditary cancer-predisposing syndrome	2016-03-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034396	SCV001154477	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	APC: BP4, BS1
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034396	SCV002010864	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000247116	SCV002069710	likely benign	not specified	2020-02-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115115	SCV002534529	likely benign	Hereditary cancer-predisposing syndrome	2021-02-24	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000247116	SCV002550648	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504864	SCV002807744	likely benign	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2021-12-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000119123	SCV004018829	benign	Familial adenomatous polyposis 1	2023-02-23	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115115	SCV004227997	benign	Hereditary cancer-predisposing syndrome	2023-10-31	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034396	SCV000043135	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	RCV001354019	SCV000591201	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Ala2274Val variant was identified in 3 of 2526 proband chromosomes (frequency: 0.001) from individuals or families with FAP and was not identified in 1938 control chromosomes from healthy individuals (Azzopardi 2008, Johnston 2012). The variant was also identified in dbSNP (ID: rs34919187) as "With Uncertain significance allele", ClinVar (classified as benign by Invitae; as likely benign by nine submitters), COGR, MutDB, LOVD 3.0 (3x), UMD-LSDB (4x as unclassified variant), and in Zhejiang University (1x) database. In UMD the variant was identified with a co-occurring pathogenic APC variant (c.3799dup, p.Thr1267AsnfsX9), increasing the likelihood that the p.Ala2274Val variant does not have clinical significance. The variant was not identified in Cosmic database. The variant was identified in control databases in 295 of 276782 chromosomes at a frequency of 0.001 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 2 of 24012 chromosomes (freq: 0.00008), Other in 14 of 6458 chromosomes (freq: 0.002), Latino in 56 of 34384 chromosomes (freq: 0.002), European in 152 of 126370 chromosomes (freq: 0.001), Ashkenazi Jewish in 66 of 10134 chromosomes (freq: 0.007), and South Asian in 5 of 30780 chromosomes (freq: 0.0002), while the variant was not observed in the East Asian, or Finnish populations. The p.Ala2274 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. 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.
Clinical Genetics, Academic Medical Center	RCV000034396	SCV001925922	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000034396	SCV001953850	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000034396	SCV001968987	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000034396	SCV001977642	likely benign	not provided		no assertion criteria provided	clinical testing