ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7797A>C (p.Lys2599Asn) (rs730881267)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211936 SCV000209554 uncertain significance not provided 2017-09-26 criteria provided, single submitter clinical testing This variant is denoted APC c.7797A>C at the cDNA level, p.Lys2599Asn (K2599N) at the protein level, and results in the change of a Lysine to an Asparagine (AAA>AAC). This variant has been observed in at least one individual with a Lynch syndrome-related tumor and/or colon polyps (Yurgelun 2015). APC Lys2599Asn was not observed at a significant frequency in large population cohorts (Lek 2016). Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Lys2599Asn occurs at a position that is not conserved and is located in the EB1 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 Lys2599Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159578 SCV000216437 uncertain significance Hereditary cancer-predisposing syndrome 2015-04-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000646394 SCV000768163 uncertain significance Familial adenomatous polyposis 1 2018-07-05 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 2599 of the APC protein (p.Lys2599Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs730881267, ExAC 0.009%). This variant has been observed in an individual with history of Lynch syndrome associated cancers and/or polyps (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 181826). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.

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