ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4375_4377del (p.Thr1459del) (rs386833393)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000034416 SCV000149002 uncertain significance not provided 2018-09-10 criteria provided, single submitter clinical testing This in-frame deletion of three nucleotides in APC is denoted c.4375_4377delACT at the cDNA level and p.Thr1459del (T1459del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACCT[delACT]GCTG. This variant was observed in 1/572 individuals with atherosclerosis undergoing whole exome sequencing with no specific information about cancer history (Johnston 2012). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). This deletion of a single Threonine amino acid is located in the 20-aa repeat B-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider APC Thr1459del to be a variant of uncertain significance.
Ambry Genetics RCV000567010 SCV000667732 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000567010 SCV000905984 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-07 criteria provided, single submitter clinical testing
Invitae RCV000817535 SCV000958101 uncertain significance Familial adenomatous polyposis 1 2018-07-13 criteria provided, single submitter clinical testing This variant, c.4375_4377delACT, results in the deletion of 1 amino acid of the APC protein (p.Thr1459del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs751312854, ExAC 0.001%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 41531). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. 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.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034416 SCV000043128 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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