ClinVar Miner

Submissions for variant NM_000038.6(APC):c.669A>C (p.Gln223His) (rs769482880)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163884 SCV000214474 likely benign Hereditary cancer-predisposing syndrome 2020-09-30 criteria provided, single submitter clinical testing Other data supporting benign classification;Subpopulation frequency in support of benign classification
Counsyl RCV000411931 SCV000489302 uncertain significance Familial adenomatous polyposis 1 2016-09-19 criteria provided, single submitter clinical testing
Invitae RCV000411931 SCV000552448 uncertain significance Familial adenomatous polyposis 1 2020-10-03 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 223 of the APC protein (p.Gln223His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs769482880, ExAC 0.005%). This variant has been reported in an individual who underwent testing for familial adenomatous polyposis (PMID: 23159591). ClinVar contains an entry for this variant (Variation ID: 184601). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000163884 SCV000687091 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-21 criteria provided, single submitter clinical testing This missense variant replaces glutamine with histidine at codon 223 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual being evaluated for familial adenomatous polyposis (PMID: 23159591). This variant has been identified in 4/251000 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 RCV001358755 SCV001554612 uncertain significance not specified 2021-03-31 criteria provided, single submitter clinical testing Variant summary: APC c.669A>C (p.Gln223His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251000 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.669A>C has been reported in the literature as a VUS in one individual undergoing testing for APC gene analysis (example, Kerr_2013). 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=3; likely benign, n=1). Most submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.

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