Submissions for variant NM_000038.6(APC):c.7540A>G (p.Thr2514Ala)

gnomAD frequency: 0.00004  dbSNP: rs545125246

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002523368	SCV000552545	uncertain significance	Familial adenomatous polyposis 1	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2514 of the APC protein (p.Thr2514Ala). This variant is present in population databases (rs545125246, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 33646313). ClinVar contains an entry for this variant (Variation ID: 411403). 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.
Ambry Genetics	RCV000575061	SCV000676379	likely benign	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001764443	SCV002008771	uncertain significance	not provided	2023-11-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (PMID: 33646313); This variant is associated with the following publications: (PMID: 33646313)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778967	SCV002014914	uncertain significance	not specified	2021-10-15	criteria provided, single submitter	clinical testing	Variant summary: APC c.7540A>G (p.Thr2514Ala) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251098 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge c.7540A>G has not been reported in the literature in individuals affected with Familial Adenomatous Polyposis. At least one individual affected with breast cancer has been identifeid with this variant (George_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001778967	SCV002046246	uncertain significance	not specified	2020-09-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409635	SCV004116323	uncertain significance	APC-related condition	2023-02-08	criteria provided, single submitter	clinical testing	The APC c.7540A>G variant is predicted to result in the amino acid substitution p.Thr2514Ala. This variant has been reported in an individual with breast cancer (eTable 3,George et al. 2021. PubMed ID: 33646313). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112178831-A-G) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/411403/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV002523368	SCV004199510	uncertain significance	Familial adenomatous polyposis 1	2023-10-09	criteria provided, single submitter	clinical testing