Submissions for variant NM_000038.6(APC):c.2545G>A (p.Asp849Asn)

gnomAD frequency: 0.00001  dbSNP: rs752193945

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004568866	SCV000647243	uncertain significance	Familial adenomatous polyposis 1	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 849 of the APC protein (p.Asp849Asn). This variant is present in population databases (rs752193945, 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: 469753). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Color Diagnostics, LLC DBA Color Health	RCV000580265	SCV000681530	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-18	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 849 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251180 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.
Ambry Genetics	RCV000580265	SCV001176759	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-13	criteria provided, single submitter	clinical testing	The p.D849N variant (also known as c.2545G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 2545. The aspartic acid at codon 849 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237916	SCV002010894	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307540	SCV002600806	uncertain significance	not specified	2022-10-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004806427	SCV005425889	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-04-17	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 849 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251180 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.