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 The p.S53T variant (also known as c.157T>A), located in coding exon 1 of the CHEK2 gene, results from a T to A substitution at nucleotide position 157. The serine at codon 53 is replaced by threonine, an amino acid with similar properties. This alteration was detected by genome sequencing in an ancestrally diverse cohort of 681 healthy individuals (Bodian DL et al. PLoS One. 2014 Apr 11;9(4):e94554). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000766741 SCV000278919 uncertain significance not provided 2021-07-15 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in healthy individuals undergoing whole genome sequencing (Bodian 2014); This variant is associated with the following publications: (PMID: 22114986, 11733767, 27535533, 30344923, 24728327, 22419737, 31398194)
Invitae RCV000231176 SCV000289671 uncertain significance Familial cancer of breast 2020-10-05 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 Health, Inc RCV000132037 SCV000684610 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-22 criteria provided, single submitter clinical testing This missense variant replaces serine with threonine at codon 53 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a healthy individual (PMID: 24728327). This variant has been identified in 12/251418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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; Bone 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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