ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.505T>C (p.Phe169Leu)

dbSNP: rs876659653
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487064 SCV000564871 uncertain significance not provided 2014-10-16 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.505T>C at the cDNA level, p.Phe169Leu (F169L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Phe169Leu 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 Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Phe169Leu occurs at a position that is well conserved across species and is located in the Forkhead associated (FHA) domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CHEK2 Phe169Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV003380585 SCV004092477 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-18 criteria provided, single submitter clinical testing The p.F169L variant (also known as c.505T>C), located in coding exon 3 of the CHEK2 gene, results from a T to C substitution at nucleotide position 505. The phenylalanine at codon 169 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV003766655 SCV004677258 uncertain significance Familial cancer of breast 2023-06-02 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with CHEK2-related conditions (PMID: 34903604). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 169 of the CHEK2 protein (p.Phe169Leu). ClinVar contains an entry for this variant (Variation ID: 418128). 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. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 34903604). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive.

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