ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.400G>C (p.Asp134His) (rs372874441)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212415 SCV000149922 uncertain significance not provided 2017-07-31 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.400G>C at the cDNA level, p.Asp134His (D134H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Asp134His was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Aspartic Acid and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Asp134His occurs at a position that is conserved in mammals and is located in the forkhead-associated (FHA) domain (Roeb 2012). 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 CHEK2 Asp134His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000116013 SCV000184367 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000473822 SCV000550526 uncertain significance Familial cancer of breast 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 134 of the CHEK2 protein (p.Asp134His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs372874441, ExAC 0.001%). This variant has been observed in an individual affected with colorectal cancer (PMID: 30730459). ClinVar contains an entry for this variant (Variation ID: 128072). 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: "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.
Mendelics RCV000473822 SCV000839493 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765625 SCV000896950 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000116013 SCV001349570 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-16 criteria provided, single submitter clinical testing

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