Submissions for variant NM_000038.6(APC):c.3016C>T (p.His1006Tyr)

gnomAD frequency: 0.00001  dbSNP: rs879253876

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236071	SCV000292452	uncertain significance	not provided	2016-02-29	criteria provided, single submitter	clinical testing	This variant is denoted APC c.3016C>T at the cDNA level, p.His1006Tyr (H1006Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT). This variant has not, to our knowledge, been published in the literature as a pathogenic variant or a benign polymorphism. APC His1006Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC His1006Tyr occurs at a position that is conserved across species and is located within the region responsible for down regulation through a process mediated by direct ubiquitination (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC His1006Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV002518419	SCV000818510	uncertain significance	Familial adenomatous polyposis 1	2021-09-07	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with tyrosine at codon 1006 of the APC protein (p.His1006Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 243107). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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 Diagnostics, LLC DBA Color Health	RCV001178638	SCV001343139	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1006 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 not been reported in individuals affected with APC-related disorders 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.
Ambry Genetics	RCV001178638	SCV002753366	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-03	criteria provided, single submitter	clinical testing	The p.H1006Y variant (also known as c.3016C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3016. The histidine at codon 1006 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.