Submissions for variant NM_000038.6(APC):c.2830A>G (p.Asn944Asp)

gnomAD frequency: 0.00001  dbSNP: rs749720558

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003651950	SCV000647272	uncertain significance	Familial adenomatous polyposis 1	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 944 of the APC protein (p.Asn944Asp). This variant is present in population databases (rs749720558, 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: 469775). 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	RCV000559483	SCV000786419	uncertain significance	Familial adenomatous polyposis 1	2018-05-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001555491	SCV001776924	uncertain significance	not provided	2020-06-03	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including colorectal cancer (Thutkawkorapin 2019); This variant is associated with the following publications: (PMID: 30809968)
Ambry Genetics	RCV002438446	SCV002746745	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-11	criteria provided, single submitter	clinical testing	The p.N944D variant (also known as c.2830A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 2830. The asparagine at codon 944 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration was identified in a cohort of early-onset colorectal cancer patients undergoing whole exome sequencing (Thutkawkorapin J et al. Mol Genet Genomic Med, 2019 05;7:e605). This amino acid position is not 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.
Myriad Genetics, Inc.	RCV000559483	SCV004018419	uncertain significance	Familial adenomatous polyposis 1	2023-02-14	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.
Color Diagnostics, LLC DBA Color Health	RCV002438446	SCV004361167	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-07	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 944 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 colorectal cancer (PMID: 30809968). This variant has been identified in 2/250782 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.