Submissions for variant NM_000038.6(APC):c.3425A>G (p.Asn1142Ser)

dbSNP: rs138410865

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507835	SCV000600081	uncertain significance	not specified	2016-11-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575101	SCV000675901	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-26	criteria provided, single submitter	clinical testing	The p.N1142S variant (also known as c.3425A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 3425. The asparagine at codon 1142 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly 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	RCV002527335	SCV000768029	uncertain significance	Familial adenomatous polyposis 1	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1142 of the APC protein (p.Asn1142Ser). This variant is present in population databases (rs138410865, gnomAD 0.002%). 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: 438875). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000507835	SCV001363503	uncertain significance	not specified	2019-03-25	criteria provided, single submitter	clinical testing	Variant summary: APC c.3425A>G (p.Asn1142Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 245736 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant of interest has been reported in the literature in individuals refered for testing (Tung_2015). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000575101	SCV002052621	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 1142 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 been reported in an individual affected with breast cancer (PMID: 25186627). This variant has been identified in 2/250982 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.
Mendelics	RCV000507835	SCV002516880	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
GeneDx	RCV003314601	SCV004014198	uncertain significance	not provided	2023-07-11	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; Observed in an individual with breast cancer (Tung et al., 2015); This variant is associated with the following publications: (PMID: 18199528, 25186627)
Baylor Genetics	RCV002527335	SCV004201993	uncertain significance	Familial adenomatous polyposis 1	2023-08-20	criteria provided, single submitter	clinical testing