ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1283C>T (p.Ser428Phe) (rs137853011)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115994 SCV000187227 pathogenic Hereditary cancer-predisposing syndrome 2017-11-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification,Significant disease association in appropriately sized case-control study(ies),Good segregation with disease (lod 1.5-3 = 5-9 meioses),Deficient protein function in appropriate functional assay(s)
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212459 SCV000892318 likely pathogenic not provided 2018-09-30 criteria provided, single submitter clinical testing
Color RCV000115994 SCV000292126 pathogenic Hereditary cancer-predisposing syndrome 2015-02-16 criteria provided, single submitter clinical testing
Counsyl RCV000197718 SCV000677740 likely pathogenic Familial cancer of breast 2017-05-22 criteria provided, single submitter clinical testing S428F has a reduced penetrance compared to the pathogenic CHEK2 mutation, c.1100delC, and is estimated to confer approximately a two-fold increased risk of breast cancer in the Ashkenazi Jewish population.
Fulgent Genetics,Fulgent Genetics RCV000515286 SCV000611259 pathogenic Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000212459 SCV000149903 pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing This pathogenic variant is denoted CHEK2 c.1283C>T at the cDNA level, p.Ser428Phe (S428F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). Functional studies revealed this variant to have loss of CHEK2-mediated DNA damage response (Roeb 2012) and to impair protein function in yeast complementation assays (Shaag 2005, Tischkowitz 2008). Shaag et al. (2005) identified this variant in 47/1,632 Ashkenazi Jewish women with breast cancer and 23/1,673 unaffected controls, conferring a 2-fold increased risk for breast cancer in the Ashkenazi Jewish women with this variant. CHEK2 Ser428Phe has been reported to co-segregate with breast cancer in at least three families (Laitman 2007, Roeb 2012). Finally, loss of heterozygosity was observed in breast tumors from two individuals heterozygous for CHEK2 Ser428Phe, suggesting this variant may be involved in tumor growth (Shaag 2005). Although this variant was observed in large population cohorts, data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). CHEK2 Ser428Phe is located within the kinase domain (Cai 2009, Roeb 2012). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
GeneKor MSA RCV000115994 SCV000821728 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000005953 SCV000594114 pathogenic Breast cancer, susceptibility to 2017-02-21 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000197718 SCV000839938 pathogenic Familial cancer of breast 2017-06-05 criteria provided, single submitter clinical testing The c.1283C>T (p.Ser428Phe) variant in the CHEK2 gene has been reported in patients with breast cancer [PMID 15649950, 22419737]. The variant was detected at a frequency of about 3% among Ashkenazi-Jewish female patients with breast cancer as opposed to 1.4% in controls (odds ratio of 2.13) [PMID 15649950]. The study concluded that this specific variant increases the breast cancer risk by 2-fold among Ashkenazi Jewish women. A family was also reported with two breast cancer female siblings heterozygous for the variant while two additional family members, also heterozygous for the variant, were asymptomatic at 58 and 60 years old and one heterozygous female member had esophageal cancer [PMID 22419737]. This variant is located in the kinase domain and functional assays in yeast showed that the mutant allele disrupt the the normal function of CHEK2 [PMID 15649950]. This variant was reported in 37 heterozygous European and South Asian individuals in ExAC (http://exac.broadinstitute.org/variant/22-29091207-G-A). Serine at amino acid position 428 of the CHEK2 protein is conserved in mammals. While not validated for clinical use, computer-based algorithms (SIFT and Polyphen-2) predict this p.Ser428Phe change to be deleterious. It is thus classified as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000388223 SCV000437715 pathogenic Neoplasm of the breast 2016-06-14 criteria provided, single submitter clinical testing The c.1283C>T (p.Ser428Phe) variant is well described in the literature, and is thought to be a founder variant in the Ashkenazi Jewish population (Shaag et al. 2005). This variant is a low penetrance allele, resulting in a two-fold increase in breast cancer risk for women over 50. The p.Ser428Phe variant was first identified in a study by Shaag et al. (2005) in which it was detected in a heterozygous state in 47 out of 1632 probands, and in 23 of the 1673 controls. The association with breast cancer was statistically significant (OR = 2.13, p=0.004). The variant was found in two additional studies in at least 12 probands with breast cancer, ten of whom also carried an intronic variant that is thought to be benign (Walsh et al. 2006; Laitman et al. 2007). Segregation with disease was demonstrated within three families. Roeb et al. (2012) identified the variant in six individuals in one family, where two carriers had breast cancer and one had esophageal cancer. Two of the other unaffected carriers were younger than 50. The variant is reported at a frequency of 0.00055 in the European (Non-Finnish) population of the Exome Aggregation Consortium. The p.Ser428Phe variant occurs at a position that is conserved in mammals and is located within the kinase domain (Roeb et al. 2012). Functional studies in yeast based on a lack of complementation of RAD53 demonstrated that the variant abrogates CHEK2 function (Shaag et al. 2005; Tischkowitz et al. 2008; Roeb et al. 2012). Based on the evidence, the p.Ser428Phe variant is classified as pathogenic for breast cancer but is considered to be a low penetrance risk allele.
Illumina Clinical Services Laboratory,Illumina RCV000277703 SCV000437716 uncertain significance Colorectal cancer 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778654 SCV000914987 pathogenic CHEK2-Related Cancer Susceptibility 2017-09-05 criteria provided, single submitter clinical testing The CHEK2 c.1283C>T (p.Ser428Phe) missense variant is well described in the literature, and is thought to be a founder variant in the Ashkenazi Jewish population (Shaag et al. 2005). This variant is a low penetrance allele, expecting to result in a two-fold increase in breast cancer risk for women over 50. The p.Ser428Phe variant was first identified in a study by Shaag et al. (2005) in which it was detected in a heterozygous state in 47 out of 1632 female Ashkenazi Jewish probands with breast cancer (unselected for family history or age at diagnosis), and in 23 of the 1673 controls. The association with breast cancer was statistically significant (OR = 2.13, p=0.004). The variant was found in two additional studies in at least 12 female probands with breast cancer, ten of whom also carried an intronic variant that is thought to be benign (Walsh et al. 2006; Laitman et al. 2007). Segregation with disease was demonstrated within three families. Roeb et al. (2012) identified the variant in six individuals in one family, where two of these individuals had breast cancer and one had esophageal cancer. Two of the other unaffected carriers were younger than 50 years old. The variant is reported at a frequency of 0.00055 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Ser428Phe variant occurs at a position that is conserved in mammals and is located within the kinase domain (Roeb et al. 2012). Functional studies in yeast based on a lack of complementation of RAD53 demonstrated that the variant abrogates CHEK2 function (Shaag et al. 2005; Tischkowitz et al. 2008; Roeb et al. 2012). Based on the evidence, the p.Ser428Phe variant is classified as pathogenic for CHEK2-related cancer susceptibility, but is considered to be a low penetrance risk allele. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000586482 SCV000698769 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-11 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.1283C>T (p.Ser428Phe) variant involves the alteration of a conserved nucleotide in protein kinase domain. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 73/134556 control chromosomes at a frequency of 0.0005425, predominantly in individuals of European or Ashkenazi Jewish descent at 0.055% and 0.68%, respectively. These frequencies exceed the maximal expected allele frequency for a pathogenic variant in CHEK2 (0.031%), suggesting this variant may be a benign polymorphism. Although 2 research groups (Tischkowitz et al, 2008 and Roeb et al., 2012) indicated that S428F failed to segregate with the disease in 1 BrC and 2 PrCa families, this variant has been identfied in multiple affected individuals (predominantly of AJ ancestry) presented with HBOC and was reported to segregate with the disease in at least 3 families with more than 3 affected individuals per family being confirmed to be a carrier of S428F. At-least one case-control studies (Shaag et al. 2005 and Tischkowitz et al 2008) estimated that this mutation confers a moderate risk (odds ratio 2.13, 95% confidence interval 1.263.69; P = 0.004) for developing breast cancer among Ashkenazi Jewish individuals. In functional studies by several independent research groups, this variant showed a reduced ability to complement the lethality of a Rad53 deletion in the yeast S. cerevisiae. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Invitae RCV000197718 SCV000253983 pathogenic Familial cancer of breast 2019-01-08 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 428 of the CHEK2 protein (p.Ser428Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs137853011, ExAC 0.06%). In a large case-control study of Ashkenazi Jewish women, this variant was found in 2.9% of individuals with breast cancer and 1.4% of individuals with no prior indication of cancer. This translates to ~2-fold increased risk (OR=2.13, 95% CI [1.26, 3.69], P=0.004) of breast cancer for c.1283C>T carriers in this population (PMID: 15649950). Outside of the Ashkenazi Jewish population this variant is very rare (<0.05%) and the cancer risks have not been well established. It has been reported in two sisters with breast cancer (ages 41 and 51), although their mother did not develop cancer before passing away at 83 (PMID: 22419737). Their aunt and two female cousins also carried this variant; the aunt had a history of esophageal cancer (at age 76) while the cousins (ages 58 and 60) did not have any prior indication of cancer (PMID: 22419737). ClinVar contains an entry for this variant (Variation ID: 5603). Experimental studies in yeast have shown that the Ser428Phe substitution abrogates CHEK2 protein function to a similar extent as other partially damaging alleles (PMID: 15649950, 22419737). Furthermore, in two individuals with invasive breast cancer, this missense variant was found to be heterozygous in the germline and hemizygous in the tumors (PMID: 15649950). Altogether, these results suggest that the Ser428Phe change is deleterious and contributes to tumorigenesis. In summary, this variant is reported to cause an increased risk for cancer. However, since this variant is associated with a much lower risk than other Pathogenic alleles in the CHEK2 gene, it has been classified as Pathogenic (low penetrance).
Mendelics RCV000197718 SCV000839461 pathogenic Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
OMIM RCV000005953 SCV000026135 risk factor Breast cancer, susceptibility to 2005-02-15 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212459 SCV000601148 likely pathogenic not provided 2017-01-23 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000210180 SCV000266068 pathogenic Breast and colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing

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