ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.157T>A (p.Ser53Thr) (rs371657037)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132037 SCV000187096 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);Other data supporting benign classification
GeneDx RCV000766741 SCV000278919 uncertain significance not provided 2019-01-10 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.157T>A at the cDNA level, p.Ser53Thr (S53T) at the protein level, and results in the change of a Serine to a Threonine (TCT>ACT). This variant was identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. CHEK2 Ser53Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the SQ/TQ motif (Bartek 2001, Desrichard 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CHEK2 Ser53Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000231176 SCV000289671 uncertain significance Familial cancer of breast 2019-11-30 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 53 of the CHEK2 protein (p.Ser53Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs371657037, ExAC 0.006%). This variant has been observed in an individual affected with Wilms tumor (PMID: 30344923). ClinVar contains an entry for this variant (Variation ID: 133888). 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: "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.
Illumina Clinical Services Laboratory,Illumina RCV000354036 SCV000437729 uncertain significance CHEK2-Related Cancer Susceptibility 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl RCV000231176 SCV000489481 uncertain significance Familial cancer of breast 2016-10-11 criteria provided, single submitter clinical testing
Color RCV000132037 SCV000684610 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-04 criteria provided, single submitter clinical testing
Mendelics RCV000231176 SCV000839504 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765627 SCV000896952 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
ITMI RCV000120553 SCV000084707 not provided not specified 2013-09-19 no assertion provided reference population

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