ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7415C>T (p.Ala2472Val) (rs200399245)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122799 SCV000166056 likely benign Familial adenomatous polyposis 1 2019-12-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000164132 SCV000214747 likely benign Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Co-occurence with mutation in same gene (phase unknown)
GeneDx RCV000034398 SCV000293281 uncertain significance not provided 2018-05-21 criteria provided, single submitter clinical testing This variant is denoted APC c.7415C>T at the cDNA level, p.Ala2472Val (A2472V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). APC Ala2472Val has been reported in a patient with colorectal cancer (Yurgelun 2017), in two patients with breast and/or ovarian cancer (Maxwell 2016), and in two individuals with no specific information provided regarding cancer history (Johnston 2012, Rodriguez-Flores 2014). APC Ala2472Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). APC Ala2472Val is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Ala2472Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000408370 SCV000452045 likely benign APC-Associated Polyposis Disorders 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000122799 SCV000488669 uncertain significance Familial adenomatous polyposis 1 2016-05-20 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000235447 SCV000593261 uncertain significance not specified 2016-08-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235447 SCV000600147 uncertain significance not specified 2017-07-12 criteria provided, single submitter clinical testing
Color RCV000164132 SCV000681865 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-17 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000034398 SCV000883408 uncertain significance not provided 2018-03-29 criteria provided, single submitter clinical testing The APC c.7415C>T; p.Ala2472Val variant (rs200399245) is reported in the medical literature in two individuals with breast cancer (Maxwell 2016) and in one individual with colorectal cancer (Yurgelun 2016). However, the variant is also described in individuals not selected for a personal or family history of cancer (Johnston 2012, Rodriguez-Flores 2014). The variant is reported in the ClinVar database (Variation ID: 41513). The variant is also listed in the Genome Aggregation Database in 9/276906 alleles. The alanine at this position is weakly conserved across species and computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. Considering available information, there is insufficient evidence to classify this variant with certainty. However, the vast majority of pathogenic APC variants are truncating nonsense or frameshift variants (see InSiGHt, Kerr 2013). Pathogenic APC variants are causative for adenomatous polyposis coli (MIM: 175100). References: Link to InSiGHt: Johnston JJ et al. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet. 2012 Jul 13;91(1):97-108. 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. Maxwell KN et al. Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. Am J Hum Genet. 2016 May 5;98(5):801-817. Rodriguez-Flores JL et al. Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar. Hum Mutat. 2014 Jan;35(1):105-16. Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095.
Integrated Genetics/Laboratory Corporation of America RCV000235447 SCV001337711 uncertain significance not specified 2020-01-27 criteria provided, single submitter clinical testing Variant summary: APC c.7415C>T (p.Ala2472Val) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251162 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (4e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.7415C>T has been reported in the literature in an individual affected with colorectal cancer (Yurgelun_2017) and individuals with breast cancer (Tung_2015) without strong evidence for causality. 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. Nine other ClinVar submitters (evaluation after 2014) have cited the variant as uncertain significance (n=7) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034398 SCV000043138 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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