ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6821C>T (p.Ala2274Val) (rs34919187)

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Total submissions: 17
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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 RCV000119123 SCV000153837 benign Familial adenomatous polyposis 1 2020-12-07 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 Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Subpopulation frequency in support of benign classification
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,PreventionGenetics RCV000247116 SCV000301604 likely benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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: 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
PreventionGenetics,PreventionGenetics RCV000034396 SCV000805458 likely benign not provided 2015-05-06 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 2018-07-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115115 SCV000902580 benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034396 SCV001154477 likely benign not provided 2021-01-01 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
Human Genetics - Radboudumc,Radboudumc RCV000034396 SCV001953850 likely benign not provided no assertion criteria provided clinical testing

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