ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2444A>C (p.Asn815Thr)

gnomAD frequency: 0.00002  dbSNP: rs762990578
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197360 SCV000254000 likely benign Familial adenomatous polyposis 1 2024-01-29 criteria provided, single submitter clinical testing
Counsyl RCV000197360 SCV000488943 uncertain significance Familial adenomatous polyposis 1 2016-07-26 criteria provided, single submitter clinical testing
GeneDx RCV000493690 SCV000581705 uncertain significance not provided 2023-07-25 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28481359)
Ambry Genetics RCV000563002 SCV000667316 likely benign Hereditary cancer-predisposing syndrome 2017-01-05 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Preventiongenetics, part of Exact Sciences RCV000493690 SCV000805381 uncertain significance not provided 2017-10-16 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000563002 SCV000910971 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-26 criteria provided, single submitter clinical testing This missense variant replaces asparagine with threonine at codon 815 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 hereditary cancer in the literature. This variant has been identified in 7/282288 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.
Illumina Laboratory Services, Illumina RCV001155356 SCV001316780 uncertain significance APC-Associated Polyposis Disorders 2018-01-12 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192829 SCV001361208 uncertain significance not specified 2019-08-09 criteria provided, single submitter clinical testing Variant summary: APC c.2444A>C (p.Asn815Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250882 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2444A>C in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (4x VUS, 2x likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc. RCV000197360 SCV004017869 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.
True Health Diagnostics RCV000563002 SCV000805206 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 no assertion criteria provided clinical testing

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