ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3426T>A (p.Asn1142Lys) (rs375478525)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130415 SCV000185277 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000235983 SCV000292455 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing This variant is denoted APC c.3426T>A at the cDNA level, p.Asn1142Lys (N1142K) at the protein level, and results in the change of an Asparagine to a Lysine (AAT>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Asn1142Lys was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Asn1142Lys occurs at a position that is conserved across species and is located in a Beta-catenin 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 Asn1142Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000130415 SCV000681599 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing
Invitae RCV000813483 SCV000953844 uncertain significance Familial adenomatous polyposis 1 2018-07-10 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 1142 of the APC protein (p.Asn1142Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs375478525, ExAC 0.003%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 141774). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.

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