ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1312G>T (p.Asp438Tyr) (rs200050883)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587890 SCV000149905 uncertain significance not provided 2021-06-30 criteria provided, single submitter clinical testing Published functional studies are inconclusive/conflicting: demonstrates kinase activity comparable to wildtype in a cell-based assay while results of in vitro assays are inconsistent (Bell 2007, Delimitsou 2019, Kleiblova 2019); Observed in individuals with a personal and/or family history of breast, prostate, colorectal, or endometrial cancer (Seppala 2003, Bell 2007, Tischkowitz 2008, Baloch 2014, Tung 2015, Ring 2016, Kayser 2018, Fanale 2020, Grasel 2020, Moradian 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.1441G>T, p.Asp481Tyr; This variant is associated with the following publications: (PMID: 14612911, 15087378, 28828701, 28776603, 28873162, 24390236, 17721994, 18571837, 23960188, 21244692, 27067391, 26787654, 28553140, 25186627, 27153395, 27498913, 27878467, 28452373, 19768534, 29335925, 27595995, 27443514, 29987844, 29484706, 30344923, 28301460, 30851065, 29875428, 29522266, 31050813, 31398194, 31159747, 28779002, 31220302, 33134171, 33322746, 27535533, 32854451, 33558524, 22419737, 19782031, 27009842, 32906215)
Ambry Genetics RCV000115996 SCV000172942 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-06 criteria provided, single submitter clinical testing The p.D438Y variant (also known as c.1312G>T), located in coding exon 11 of the CHEK2 gene, results from a G to T substitution at nucleotide position 1312. The aspartic acid at codon 438 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been identified in multiple prostate cancer cohorts, but was not detected in a multi-ethnic breast cancer series of over 2000 cases (Southey MC et al. J. Med. Genet. 2016 Dec;53:800-811; Seppälä EH et al. Br. J. Cancer. 2003 Nov;89:1966-70; Bell DW et al. Int. J. Cancer. 2007 Dec;121:2661-7; Tischkowitz MD et al. Cancer Lett. 2008 Oct;270:173-80). This alteration was seen in 1/70 breast cancer patients from Balochistan, but was not observed in 70 controls (Baloch AH et al. Mol. Biol. Rep. 2014 Feb;41:1103-7). In another study, this variant was observed in 2/1303 female breast cancer patients and 2/1109 unaffected female controls (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6). This alteration has also been identified in a male breast cancer proband (Fostira F et al. Breast Cancer Res. Treat. 2018 May;169:105-113). Functional analysis of p.D438Y performed by Bell et al. demonstrated intact protein stability and reduced, but not absent, kinase activity on the CHK2 substrate BRCA1 (Bell DW et al. Int. J. Cancer. 2007 Dec;121:2661-7). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat. 2019 05;40:631-648). Another functional study found normal KAP1 phosphorylation in a human cell-based assay but intermediate kinase activity in the in vitro kinase assay (Kleiblova P et al. Int. J. Cancer. 2019 Oct;145:1782-1797). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000199565 SCV000254923 likely benign Familial cancer of breast 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000199565 SCV000489071 uncertain significance Familial cancer of breast 2016-08-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115996 SCV000537526 likely benign Hereditary cancer-predisposing syndrome 2019-08-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587890 SCV000601150 uncertain significance not provided 2020-02-06 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515311 SCV000611451 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000200982 SCV000698770 uncertain significance not specified 2021-06-02 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1312G>T (p.Asp438Tyr) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 261860 control chromosomes, predominantly at a frequency of 0.00046 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5- fold 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 Non-Finnish European origin. However, the frequency in gnomAD and the cases reported in the literature may not be accurate due to the sequencing technology used being unable to distinguish between CHEK2 and its multiple overlapping pseudogenes. c.1312G>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, but also in controls and in a family where it did not segregate with disease (examples- Baloch_2013, Bell_2007, LeCalvez-Kelm_2011, Seppala_2003, Tischkowitz_2008, Young_2016, Yadav_2016, Tung_2015, Maxwell_2016, Fostira_2018, Scarpetta_2019). These data thus do not allow any conclusion about variant significance. Co-occurrence with another pathogenic variant has been reported (MSH2 c.1697del, p.Asn566IlefsX24), providing supporting evidence for a benign role (Ring_2016). Case control approaches indicated no significant risk association for breast cancer, but a slightly elevated risk for prostate cancer (Le Calvez-Kelm_2011, Southey_2016). In a mammalian cell based kinase-assay the variant protein showed about 70% reduction in activity (Bell_2007), whereas in a yeast based DNA-damage assay the variant showed similar function to the wild type (Delimitsou_2019); therefore these data do not provide clear conclusions about the variant effect. 14 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as uncertain significance (n=12) and likely bening (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics,PreventionGenetics RCV000587890 SCV000806866 uncertain significance not provided 2017-08-18 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115996 SCV000821989 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000199565 SCV000839460 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587890 SCV000892301 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001147975 SCV001308835 uncertain significance CHEK2-Related Cancer Susceptibility 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Department of Pediatric Oncology, Hematology and Clinical Immunology,University Clinics Duesseldorf RCV000115996 SCV001482297 uncertain significance Hereditary cancer-predisposing syndrome criteria provided, single submitter research
Baylor Genetics RCV001294021 SCV001482780 uncertain significance Li-Fraumeni syndrome 2 2019-10-12 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GenomeConnect, ClinGen RCV000587890 SCV000986776 not provided not provided no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported most recently on 12-04-2018 by Lab or GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Center of Medical Genetics and Primary Health Care RCV000199565 SCV000987292 uncertain significance Familial cancer of breast 2020-04-08 no assertion criteria provided research ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: Pkinase domain (M265-529L aa) which contains the catalytic function of protein kinases. Hot-spot has 21 non-VUS coding variants (7 pathogenic and 14 benign), pathogenicity = 33.3%, proximity score 3.967 > threshold 2.472. PP1 Pathogenic Supporting: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PP2 Pathogenic Supporting: 30 out of 48 non-VUS missense variants in gene CHEK2 are pathogenic = 62.5% > threshold of 51.0%, and 308 out of 1,604 clinically reported variants in gene CHEK2 are pathogenic = 19.2% > threshold of 12.0%. PP1 Pathogenic Supporting: 2 patients are sibs (sisters) who share the same variant. BP4 Benign Supporting: 6 benign predictions from DEOGEN2, EIGEN, MVP, MutationAssessor, PrimateAI and REVEL vs 5 pathogenic predictions from DANN, FATHMM-MKL, M-CAP, MutationTaster and SIFT and the position is not conserved." Therefore, this variant was classified as a Variant of Unknown Significance.
Center of Medical Genetics and Primary Health Care RCV001269492 SCV001449146 likely benign Malignant tumor of breast no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356041 SCV001551095 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The CHEK2 p.Asp438Tyr variant was identified in 4 of 1332 proband chromosomes (frequency: 0.003) from Pakistani, Finnish, Polish and Ashkenazi Jewish individuals or families with breast, early onset breast and prostate, or hereditary prostate cancer and was not identified in 590 control chromosomes from healthy individuals (Baloch 2014, Seppala 2003, Tischkowitz 2008, Bell 2007). The variant was identified in dbSNP (ID: rs200050883) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Counsyl, and Color Genomics), and the Zhejiang Colon Cancer Database (14x, co-occurring with CHEK2 c.1100delC). The variant was not identified in Cosmic. The variant was identified in control databases in 108 of 276806 chromosomes at a frequency of 0.0004 (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations: European in 57 of 126326 chromosomes (frequency: 0.0005), Finnish in 33 of 25792 chromosomes (frequency: 0.001), African in 3 of 24032 chromosomes (frequency: 0.0001), Other in 4 of 6456 chromosomes (frequency: 0.0006), Latino in 2 of 34404 chromosomes (frequency: 0.00006), and South Asian in 9 of 30776 chromosomes (frequency: 0.0003). The variant occurs in the catalytic domain of the CHEK2 protein and in vitro analysis of kinase activity showed the variant had a 70% decrease in activity compared to wildtype (Baloch 2014, Bell 2007). The p.Asp438 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Tyr variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000587890 SCV001808572 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000587890 SCV001905700 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000587890 SCV001952270 uncertain significance not provided no assertion criteria provided clinical testing

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