Submissions for variant NM_000038.6(APC):c.8459C>T (p.Thr2820Ile)

dbSNP: rs200790804

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001017822	SCV001178974	uncertain significance	Hereditary cancer-predisposing syndrome	2019-07-09	criteria provided, single submitter	clinical testing	The p.T2820I variant (also known as c.8459C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 8459. The threonine at codon 2820 is replaced by isoleucine, an amino acid with similar properties. This variant was detected as a secondary finding in 1 out of 572 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for this particular individual was not provided (Johnston JJ et al. Am. J. Hum. Genet. 2012 Jul;91:97-108). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV003743554	SCV003204188	uncertain significance	Familial adenomatous polyposis 1	2022-06-09	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 41538). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2820 of the APC protein (p.Thr2820Ile).
Color Diagnostics, LLC DBA Color Health	RCV001017822	SCV004358775	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 2820 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034423	SCV000043145	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.