ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1606G>A (p.Glu536Lys) (rs138098808)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199835 SCV000253990 likely benign Familial adenomatous polyposis 1 2020-11-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000217491 SCV000273018 benign Hereditary cancer-predisposing syndrome 2020-07-13 criteria provided, single submitter clinical testing In silico models in agreement (benign);No disease association in small case-control study;Other data supporting benign classification;Subpopulation frequency in support of benign classification
GeneDx RCV000656746 SCV000292449 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing This variant is denoted APC c.1606G>A at the cDNA level, p.Glu536Lys (E536K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has been reported in an individual with colon cancer, a patient with a personal history of a Lynch syndrome-associated cancer and/or polyps, and in two individuals with breast cancer (Tung 2015, Yurgelun 2015, Pearlman 2017). APC Glu536Lys was observed at an allele frequency of 0.08% (20/24,026 alleles) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located within the armadillo region (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether APC Glu536Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235744 SCV000600046 uncertain significance not specified 2017-06-09 criteria provided, single submitter clinical testing
Color Health, Inc RCV000217491 SCV000681478 likely benign Hereditary cancer-predisposing syndrome 2020-01-24 criteria provided, single submitter clinical testing
Mendelics RCV000199835 SCV000838079 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764561 SCV000895649 uncertain significance Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235744 SCV001362483 likely benign not specified 2020-09-14 criteria provided, single submitter clinical testing Variant summary: APC c.1606G>A (p.Glu536Lys) results in a conservative amino acid change in 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 4.4e-05 in 250728 control chromosomes, predominantly at a frequency of 0.00068 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10 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 African or African-American origin. c.1606G>A has been reported in the literature in individuals affected with breast cancer, colon cancer, and in an individual with a personal- or family history of Lynch syndrome (Tung_2014, Yurgelun_2015, Pearlman_2016). 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. Seven 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 to include two submitters who have re-classified this variant as likely benign since our previous evaluation. (VUS, n=5, likely benign, n=2). Some submitters cite overlapping evidence utilized in the context of our evaluation. Based on the evidence outlined above, and the emerging transition in its classification, this variant was re-classified as likely benign.

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