ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3479C>A (p.Thr1160Lys) (rs201004111)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130655 SCV000185540 likely benign Hereditary cancer-predisposing syndrome 2018-11-29 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);in silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000034385 SCV000209515 uncertain significance not provided 2020-11-17 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal history of colorectal adenomas or colorectal cancer (Azzopardi 2008, Raskin 2017); This variant is associated with the following publications: (PMID: 30709382, 28873162, 29212164, 27600092, 27150160, 18199528, 21859464, 25637381, 22703879)
Invitae RCV000204291 SCV000259359 likely benign Familial adenomatous polyposis 1 2020-12-08 criteria provided, single submitter clinical testing
Counsyl RCV000204291 SCV000487797 uncertain significance Familial adenomatous polyposis 1 2015-11-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000235094 SCV000538297 uncertain significance not specified 2017-01-24 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: This variant is classified as DM in HGMD - it has been seen in one patient with colorectal adenoma and one unaffected patient. It has been classified with 1 star as VUS by 4 sumitters (GeneDx, Invitae, CSER_CC_NCGL, Biesecker lab) and Likely benign by 1 (Ambry). MaxMAF is 0.02% in ExAC (high for disease prevalence).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034385 SCV000600083 uncertain significance not provided 2019-01-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130655 SCV000681610 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-15 criteria provided, single submitter clinical testing This missense variant replaces threonine with lysine at codon 1160 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual each affected with familial adenomatous polyposis (PMID: 18199528), colorectal cancer (PMID: 29212164), breast cancer (PMID: 29684080) and in an individual(s) with an unspecified cancer (PMID: 28873162). This variant has also been observed in multiple individuals in the general population who were selected for phenotypes not directly related to cancer (PMID: 22703879, 25637381). This variant has been identified in 32/282180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235094 SCV000916470 likely benign not specified 2021-03-13 criteria provided, single submitter clinical testing Variant summary: APC c.3479C>A (p.Thr1160Lys) results in a non-conservative amino acid change located in the one of the 15 residue repeat domains (IPR009240) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 250788 control chromosomes, predominantly at a frequency of 0.00021 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 3 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.3479C>A has been reported in the literature in individuals affected with non-FAP non-MAP colorectal adenomas (Azzopardi 2008) and in a family with colorectal cancer without polyps (Raskin 2017). These report(s) 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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=3; VUS, n=5). At-least one submitter reports an unspecified pathogenic co-occurrence within the same gene as a basis of a likely benign outcome and some cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000204291 SCV001136903 benign Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034385 SCV000043123 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington RCV000148371 SCV000190064 uncertain significance Colorectal adenoma 2014-06-01 no assertion criteria provided research

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