Submissions for variant NM_000038.6(APC):c.5816A>T (p.Asp1939Val)

gnomAD frequency: 0.00001  dbSNP: rs754783550

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165007	SCV000215702	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	The p.D1939V variant (also known as c.5816A>T), located in coding exon 15 of the APC gene, results from an A to T substitution at nucleotide position 5816. The aspartic acid at codon 1939 is replaced by valine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463148	SCV000552670	uncertain significance	Familial adenomatous polyposis 1	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1939 of the APC protein (p.Asp1939Val). This variant is present in population databases (rs754783550, 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: 185564). 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.
GeneDx	RCV000484552	SCV000567229	uncertain significance	not provided	2019-09-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV000165007	SCV000687048	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 1939 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 not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 1/250146 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.
Counsyl	RCV000463148	SCV000785437	uncertain significance	Familial adenomatous polyposis 1	2017-08-09	criteria provided, single submitter	clinical testing
Mendelics	RCV000463148	SCV000838138	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000463148	SCV004018025	uncertain significance	Familial adenomatous polyposis 1	2023-02-16	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.
Baylor Genetics	RCV000463148	SCV004197475	uncertain significance	Familial adenomatous polyposis 1	2023-10-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995380	SCV004838108	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 1939 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 not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 1/250146 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484552	SCV005625434	uncertain significance	not provided	2024-08-14	criteria provided, single submitter	clinical testing	The APC c.5816A>T (p.Asp1939Val) variant has been reported in the published literature in individuals/families affected with breast and/or ovarian cancer (PMIDs: 35264596 (2022), 35534704 (2022), 38874686 (2024)). The frequency of this variant in the general population, 0.000004 (1/250146 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV004739523	SCV005355860	uncertain significance	APC-related disorder	2024-05-24	no assertion criteria provided	clinical testing	The APC c.5816A>T variant is predicted to result in the amino acid substitution p.Asp1939Val. This variant was identified as a variant of uncertain significance in individuals who underwent clinical testing for hereditary cancer risk (de Oliveira JM et al 2022. PubMed ID: 35534704). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD and is reported in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/185564/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.