ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4534G>A (p.Asp1512Asn) (rs778699501)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166273 SCV000217054 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-04 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000236286 SCV000293583 uncertain significance not specified 2017-03-07 criteria provided, single submitter clinical testing This variant is denoted APC c.4534G>A at the cDNA level, p.Asp1512Asn (D1512N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant has not, to our knowledge, been reported in the literature as pathogenic or benign. APC Asp1512Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Asp1512Asn occurs at a position that is conserved across species and is located in the 20-aa repeat b-catenin down-regulating domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Asp1512Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000469936 SCV000552491 uncertain significance Familial adenomatous polyposis 1 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1512 of the APC protein (p.Asp1512Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs778699501, ExAC 0.006%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 186645). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000166273 SCV000681672 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001155477 SCV001316905 uncertain significance APC-Associated Polyposis Disorders 2018-04-20 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Integrated Genetics/Laboratory Corporation of America RCV000236286 SCV001363552 uncertain significance not specified 2019-05-14 criteria provided, single submitter clinical testing Variant summary: APC c.4534G>A (p.Asp1512Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250350 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.4534G>A, has been reported in the literature in individuals affected with NSCLC or adenocarcinomas (Mambetsariev_2018, Sekine_2014). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. A co-occurrence with another pathogenic variant has been reported (APC c.1312+3A>G), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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