Submissions for variant NM_000038.6(APC):c.6223G>T (p.Asp2075Tyr)

dbSNP: rs754004343

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484199	SCV000571119	uncertain significance	not provided	2016-07-27	criteria provided, single submitter	clinical testing	This variant is denoted APC c.6223G>T at the cDNA level, p.Asp2075Tyr (D2075Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Asp2075Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Asp2075Tyr occurs at a position that is not conserved and is not located in a known functional domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Asp2075Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000775338	SCV000909610	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-09	criteria provided, single submitter	clinical testing
Invitae	RCV003651929	SCV001221872	uncertain significance	Familial adenomatous polyposis 1	2022-05-19	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. This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 2075 of the APC protein (p.Asp2075Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 421808). 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").
Ambry Genetics	RCV000775338	SCV002659796	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-27	criteria provided, single submitter	clinical testing	The p.D2075Y variant (also known as c.6223G>T), located in coding exon 15 of the APC gene, results from a G to T substitution at nucleotide position 6223. The aspartic acid at codon 2075 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. 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.