ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5072C>T (p.Pro1691Leu)

gnomAD frequency: 0.00009  dbSNP: rs1060503346
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003651884 SCV000552716 likely benign Familial adenomatous polyposis 1 2023-05-22 criteria provided, single submitter clinical testing
GeneDx RCV000480116 SCV000567574 uncertain significance not provided 2015-08-07 criteria provided, single submitter clinical testing This variant is denoted APC c.5072C>T at the cDNA level, p.Pro1691Leu (P1691L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). Although this variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism it was observed as a somatic change in two individuals with cutaneous squamous cell carcinoma (Li 2015). APC Pro1691Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Pro1691Leu occurs at a position that is conserved in mammals and is located within the 20-amino acid repeat B-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Pro1691Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV001186460 SCV001352873 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-05 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 1691 of the APC protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 13/31390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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 RCV001186460 SCV002643615 benign Hereditary cancer-predisposing syndrome 2023-09-03 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
All of Us Research Program, National Institutes of Health RCV004001972 SCV004837999 uncertain significance Classic or attenuated familial adenomatous polyposis 2023-05-08 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 1691 of the APC protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 13/31390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.

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