ClinVar Miner

Submissions for variant NM_000038.6(APC):c.221A>C (p.Glu74Ala)

gnomAD frequency: 0.00001  dbSNP: rs773347338
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484103 SCV000568182 likely benign not provided 2019-01-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002525819 SCV000647223 benign Familial adenomatous polyposis 1 2025-02-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000776474 SCV000912026 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-03 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with alanine at codon 74 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 6/251200 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 RCV000776474 SCV001175543 uncertain significance Hereditary cancer-predisposing syndrome 2024-09-13 criteria provided, single submitter clinical testing The p.E74A variant (also known as c.221A>C) is located in coding exon 3 of the APC gene. The glutamic acid at codon 74 is replaced by alanine, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 3. This amino acid position is highly conserved in available vertebrate species. Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484103 SCV004219977 uncertain significance not provided 2024-11-01 criteria provided, single submitter clinical testing The APC c.221A>C (p.Glu74Ala) variant has not been reported in individuals with APC-related conditions in the published literature. The frequency of this variant in the general population, 0.000024 (6/251200 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.

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