ClinVar Miner

Submissions for variant NM_000038.6(APC):c.447C>A (p.Asp149Glu)

gnomAD frequency: 0.00001  dbSNP: rs750821213
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000461374 SCV000552581 uncertain significance Familial adenomatous polyposis 1 2024-12-03 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 149 of the APC protein (p.Asp149Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 411430). 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.
Ambry Genetics RCV000561667 SCV000667413 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-15 criteria provided, single submitter clinical testing The p.D149E variant (also known as c.447C>A), located in coding exon 4 of the APC gene, results from a C to A substitution at nucleotide position 447. The aspartic acid at codon 149 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is not 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.
Color Diagnostics, LLC DBA Color Health RCV000561667 SCV000909231 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-24 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glutamic acid at codon 149 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 3/277578 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.
Division of Medical Genetics, University of Washington RCV000461374 SCV001434273 uncertain significance Familial adenomatous polyposis 1 2020-01-22 criteria provided, single submitter clinical testing To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an overall allele frequency of 0.00001 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. PM2; BP4
All of Us Research Program, National Institutes of Health RCV004001944 SCV004837272 uncertain significance Classic or attenuated familial adenomatous polyposis 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glutamic acid at codon 149 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/277578 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.
Baylor Genetics RCV000461374 SCV005056222 uncertain significance Familial adenomatous polyposis 1 2024-03-08 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005033996 SCV005667807 uncertain significance Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach 2024-03-13 criteria provided, single submitter clinical testing

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