ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.415T>G (p.Tyr139Asp)

dbSNP: rs730881703
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160454 SCV000211019 uncertain significance not provided 2014-09-30 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.415T>G at the cDNA level, p.Tyr139Asp (Y139D) at the protein level, and results in the change of a Tyrosine to an Aspartic Acid (TAC>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Tyr139Asp 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 Tyrosine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Tyr139Asp occurs at a position that is highly conserved in mammals and is located in 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 Tyr139Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV001021975 SCV001183658 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-16 criteria provided, single submitter clinical testing The p.Y139D variant (also known as c.415T>G), located in coding exon 2 of the CHEK2 gene, results from a T to G substitution at nucleotide position 415. The tyrosine at codon 139 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001322030 SCV001512882 uncertain significance Familial cancer of breast 2020-08-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with aspartic acid at codon 139 of the CHEK2 protein (p.Tyr139Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182454). 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. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain.

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