ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4372C>T (p.Pro1458Ser) (rs143796828)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000034415 SCV000209525 uncertain significance not provided 2017-08-25 criteria provided, single submitter clinical testing This variant is denoted APC c.4372C>T at the cDNA level, p.Pro1458Ser (P1458S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). This variant has been observed in a healthy control individual as well in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Azzopardi 2008, Johnston 2012). APC Pro1458Ser was observed at an allele frequency of 0.03% (4/11562) in individuals of Latino ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Pro1458Ser occurs at a position that is not conserved and is located in the Beta-catenin down-regulating domain (Azzopardi 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether APC Pro1458Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159555 SCV000214752 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000196865 SCV000254014 uncertain significance Familial adenomatous polyposis 1 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 1458 of the APC protein (p.Pro1458Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs143796828, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 41530). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Counsyl RCV000196865 SCV000488485 uncertain significance Familial adenomatous polyposis 1 2016-04-14 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515179 SCV000611338 uncertain significance Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma 2017-05-23 criteria provided, single submitter clinical testing
Color RCV000159555 SCV000686973 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Mendelics RCV000196865 SCV000838118 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034415 SCV000043127 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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