Submissions for variant NM_000038.6(APC):c.4693G>T (p.Asp1565Tyr)

dbSNP: rs767138124

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587652	SCV000694058	uncertain significance	not provided	2016-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001184958	SCV001351058	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 1565 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 APC-related disorders in the literature. This variant has been identified in 1/250554 chromosomes 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.
GeneDx	RCV000587652	SCV002013932	uncertain significance	not provided	2020-02-20	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800814	SCV002046318	uncertain significance	not specified	2020-10-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001184958	SCV002633908	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-13	criteria provided, single submitter	clinical testing	The p.D1565Y variant (also known as c.4693G>T), located in coding exon 15 of the APC gene, results from a G to T substitution at nucleotide position 4693. The aspartic acid at codon 1565 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. 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.
Baylor Genetics	RCV003465320	SCV004195639	uncertain significance	Familial adenomatous polyposis 1	2023-10-20	criteria provided, single submitter	clinical testing
Invitae	RCV003465320	SCV004642984	uncertain significance	Familial adenomatous polyposis 1	2023-04-14	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 495363). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is present in population databases (rs767138124, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 1565 of the APC protein (p.Asp1565Tyr). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function.