ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7570A>G (p.Lys2524Glu) (rs143060722)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211934 SCV000149031 uncertain significance not provided 2017-06-16 criteria provided, single submitter clinical testing This variant is denoted APC c.7570A>G at the cDNA level, p.Lys2524Glu (K2524E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). This variant was observed in at least one individual with a personal or family history suspicious for Lynch syndrome (Yurgelun 2015). APC Lys2524Glu was observed at an allele frequency of 0.0231% (2/8652) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Lys2524Glu occurs at a position that is conserved in mammals and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Lys2524Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115122 SCV000186733 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000409766 SCV000488490 uncertain significance Familial adenomatous polyposis 1 2016-04-14 criteria provided, single submitter clinical testing
Invitae RCV000409766 SCV000552691 uncertain significance Familial adenomatous polyposis 1 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 2524 of the APC protein (p.Lys2524Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs143060722, ExAC 0.02%). This variant has been reported in an individual undergoing Lynch syndrome testing (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127320). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly 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.
Color RCV000115122 SCV000687131 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-17 criteria provided, single submitter clinical testing

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