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
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.
Ambry Genetics RCV000115994 SCV000187227 pathogenic Hereditary cancer-predisposing syndrome 2019-10-30 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;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);Structural Evidence
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).
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
Color RCV000115994 SCV000292126 pathogenic Hereditary cancer-predisposing syndrome 2015-02-16 criteria provided, single submitter clinical testing
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
Genetic Services Laboratory, University of Chicago RCV000005953 SCV000594114 pathogenic Breast cancer, susceptibility to 2017-02-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212459 SCV000601148 likely pathogenic not provided 2019-03-22 criteria provided, single submitter clinical testing The best available variant frequency higher than the disease allele frequency. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Strong co-segregation with disease, and data include affected and unaffected individuals from multiple families.
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
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.
Integrated Genetics/Laboratory Corporation of America RCV000586482 SCV000698769 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-15 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1283C>T (p.Ser428Phe) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00056 in 292602 control chromosomes, predominantly within the Ashkenazi Jewish subpopulation at a frequency of 0.011 in the gnomAD database, including 1 homozygote. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 35 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. In addition, the variant was reported in 10/7325 European American women (i.e. with a frequency of 0.00136), who were older than 70 years of age, and never had cancer (in the FLOSSIES database). However, the variant is located in a region that is highly homologous to PMS2 pseudogenes and the technology utilized for these datasets does not rule out pseudogene interference, therefore these data might not be reliable. c.1283C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer and other tumor phenotypes who were primarily of Ashkenazi Jewish origin. These data indicate that the variant is very likely to be associated with disease. One case-control study estimated that this variant confers a moderate risk (odds ratio: 2.13) for developing breast cancer in Ashkenazi Jewish individuals (Shaag 2005). Although two research groups indicated that this variant failed to segregate with the disease in one breast cancer and two prostate cancer families, this variant has been identified in affected individuals (predominantly of AJ ancestry) presenting with HBOC and was reported to segregate with the disease in three families, where at least three affected individuals per family carried the variant (Tischkowitz 2008 and Roeb 2012). Co-occurrences with other pathogenic variants were also noted in the literature, (e.g. BRCA1 185delAG, BRCA2 6174delT and CHEK2 c.1100delC, reported by Walsh 2017), the ages at diagnosis of some of these patients were among the youngest, thus likely indicating an additive effect, rather than an evidence against pathogenicity (Walsh 2017). In functional studies by multiple independent research groups this variant showed a reduced ability to complement the lethality of a Rad53 deletion in S. cerevisiae (Shaag 2005, Tischkowitz 2008, Roeb 2012, Yilmaz 2014). In ClinVar 13 other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (10x) / likely pathogenic (3x). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneKor MSA RCV000115994 SCV000821728 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000197718 SCV000839461 pathogenic Familial cancer of breast 2018-07-02 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212459 SCV000892318 likely pathogenic not provided 2018-06-01 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.
OMIM RCV000005953 SCV000026135 risk factor Breast cancer, susceptibility to 2005-02-15 no assertion criteria provided literature only

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