Submissions for variant NM_000038.6(APC):c.8245T>A (p.Ser2749Thr)

dbSNP: rs1064794391

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481602	SCV000569040	uncertain significance	not provided	2016-08-24	criteria provided, single submitter	clinical testing	This variant is denoted APC c.8245T>A at the cDNA level, p.Ser2749Thr (S2749T) at the protein level, and results in the change of a Serine to a Threonine (TCA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Ser2749Thr 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 Serine and Threonine share similar properties, this is considered a conservative amino acid substitution. APC Ser2749Thr occurs at a position that is not conserved and is located in the EB1 binding domain (Azzopardi 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether APC Ser2749Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000567563	SCV000667560	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	clinical testing	The p.S2749T variant (also known as c.8245T>A), located in coding exon 15 of the APC gene, results from a T to A substitution at nucleotide position 8245. The serine at codon 2749 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly 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	RCV003535753	SCV000825428	uncertain significance	Familial adenomatous polyposis 1	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 2749 of the APC protein (p.Ser2749Thr). This variant is not present in population databases (gnomAD 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: 420277). 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 with a negative predictive value of 95%. 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	RCV000567563	SCV001357562	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-23	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 2749 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 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.
Baylor Genetics	RCV002526568	SCV004204041	uncertain significance	Familial adenomatous polyposis 1	2023-05-11	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493596	SCV004243265	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing