ClinVar Miner

Submissions for variant NM_000038.5(APC):c.3909A>G (p.Gln1303=) (rs746289994)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163132 SCV000213645 likely benign Hereditary cancer-predisposing syndrome 2015-03-04 criteria provided, single submitter clinical testing
Color RCV000163132 SCV000681638 likely benign Hereditary cancer-predisposing syndrome 2017-03-20 criteria provided, single submitter clinical testing
Counsyl RCV000409994 SCV000489621 likely benign Familial adenomatous polyposis 1 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000607365 SCV000728935 benign not specified 2015-06-30 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000587952 SCV000694041 uncertain significance not provided 2017-05-08 criteria provided, single submitter clinical testing Variant summary: The APC c.3909A>G (p.Gln1303Gln) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict the creation of a cyptic 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/121000 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign, without evidence to independently evaluate. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS-possibly benign.
Invitae RCV000409994 SCV000828094 uncertain significance Familial adenomatous polyposis 1 2018-06-25 criteria provided, single submitter clinical testing This sequence change affects codon 1303 of the APC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the APC protein. This variant is present in population databases (rs746289994, ExAC 0.002%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 184023). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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