Submissions for variant NM_000038.6(APC):c.7400C>T (p.Pro2467Leu)

dbSNP: rs758713824

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000200356	SCV000254036	uncertain significance	Familial adenomatous polyposis 1	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2467 of the APC protein (p.Pro2467Leu). This variant is present in population databases (rs758713824, gnomAD 0.003%). 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: 216178). 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.
Counsyl	RCV000200356	SCV000488263	uncertain significance	Familial adenomatous polyposis 1	2016-02-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000581883	SCV000687124	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000581883	SCV001188767	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-07	criteria provided, single submitter	clinical testing	The p.P2467L variant (also known as c.7400C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 7400. The proline at codon 2467 is replaced by leucine, an amino acid with similar properties. This amino acid position is well 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175459	SCV001339032	uncertain significance	not specified	2023-08-11	criteria provided, single submitter	clinical testing	Variant summary: APC c.7400C>T (p.Pro2467Leu) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251118 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7400C>T has been reported in the literature (Rosenbluh_2016). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27684187). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV003221855	SCV003918779	uncertain significance	not provided	2023-03-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 27684187)
Myriad Genetics, Inc.	RCV002228913	SCV004019778	uncertain significance	Familial adenomatous polyposis 1	2023-02-15	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.