ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3650A>C (p.Asn1217Thr) (rs138933660)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131570 SCV000186574 likely benign Hereditary cancer-predisposing syndrome 2019-03-06 criteria provided, single submitter clinical testing In silico models in agreement (benign);Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Other data supporting benign classification
Invitae RCV000199645 SCV000254010 benign Familial adenomatous polyposis 1 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000587732 SCV000292457 likely benign not provided 2020-11-06 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19506109, 24728327, 21567896, 27978560, 28873162)
Counsyl RCV000199645 SCV000488023 uncertain significance Familial adenomatous polyposis 1 2015-12-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120014 SCV000694035 likely benign not specified 2020-09-28 criteria provided, single submitter clinical testing Variant summary: APC c.3650A>C (p.Asn1217Thr) results in a non-conservative amino acid change in 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 0.0002 in 251760 control chromosomes, predominantly at a frequency of 0.0026 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 36 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. The variant, c.3650A>C has been reported in the literature in an individual affected with cancer of cecum and also in breast cancer high-risk families. (Pearlman_2016, Bonache_2018) . However, this report does 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. Six other ClinVar submitters (evaluation after 2014) cite the variant as likely bening/benign (n=4) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000587732 SCV000805401 uncertain significance not provided 2018-01-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131570 SCV000911206 benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
ITMI RCV000120014 SCV000084144 not provided not specified 2013-09-19 no assertion provided reference population

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