Submissions for variant NM_000038.6(APC):c.8138T>C (p.Met2713Thr)

dbSNP: rs1479889029

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526686	SCV000647756	uncertain significance	Familial adenomatous polyposis 1	2022-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2713 of the APC protein (p.Met2713Thr). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 470132). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779731	SCV000916496	uncertain significance	not specified	2018-07-09	criteria provided, single submitter	clinical testing	Variant summary: APC c.8138T>C (p.Met2713Thr) results in a non-conservative amino acid change located in the EB-1 binding 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 4.1e-06 in 246116 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, no occurrence of c.8138T>C in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as "uncertian significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002420480	SCV002678970	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-30	criteria provided, single submitter	clinical testing	The p.M2713T variant (also known as c.8138T>C), located in coding exon 15 of the APC gene, results from a T to C substitution at nucleotide position 8138. The methionine at codon 2713 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). Based on the available evidence, the clinical significance of this variant remains unclear.