ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1270T>C (p.Tyr424His) (rs139366548)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590008 SCV000149902 uncertain significance not provided 2021-04-05 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function This variant is associated with the following publications: (PMID: 26580448, 32866190, 33128190, 30374176, 31784482, 31256874, 31398194, 18571837, 31050813, 22419737, 30851065, 29596542, 28779002, 30154229, 29522266, 25186627, 19782031, 25117502, 25452441, 18085035, 32546565)
Ambry Genetics RCV000115993 SCV000186576 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-26 criteria provided, single submitter clinical testing The p.Y424H variant (also known as c.1270T>C), located in coding exon 11 of the CHEK2 gene, results from a T to C substitution at nucleotide position 1270. The tyrosine at codon 424 is replaced by histidine, an amino acid with similar properties. This variant, which is present at a high frequency in the Ashkenazi Jewish sub-population, has been identified in several breast and prostate cancer families; however, it does not segregate completely with disease (Laitman Y et al. Isr. Med. Assoc. J. 2007 Nov;9:791-6; Tischkowitz MD et al. Cancer Lett. 2008 Oct;270:173-80; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Tung N et al. Cancer 2015 Jan;121(1):25-33). Yeast-based functional studies conflict about whether or not this variant is deleterious (Tischkowitz MD et al. Cancer Lett. 2008 Oct;270:173-80; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). A functional assay employing a complementation assay in human nontransformed RPE1-CHEK2-knockout cells quantifying CHK2-specific phosphorylation of endogenous protein KAP1A demonstrated <25% CHK2 kinase activity (Kleiblova P et al. Int. J. Cancer 2019 10;145(7):1782-1797). A case control study suggests that this variant is not associated with prostate cancer; however, the results were not statistically significant (Tischkowitz MD et al. Cancer Lett. 2008 Oct;270:173-80). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000197909 SCV000254922 uncertain significance Familial cancer of breast 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 424 of the CHEK2 protein (p.Tyr424His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs139366548, ExAC 0.05%). This variant was reported in families affected with breast, uterine, and prostate cancer (PMID: 18085035, 18571837, 22419737, 30374176). Currently, there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 22419737, 18571837). This variant was reported in unaffected individuals at a similar frequency to individuals with prostate cancer (PMID: 18571837). ClinVar contains an entry for this variant (Variation ID: 128054). Experimental studies have reported conflicting evidence regarding the impact of this variant on CHEK2 function in a yeast-based assay (PMID: 22419737, 18571837, 30851065). Additionally, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably 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.
Color Health, Inc RCV000115993 SCV000537514 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-19 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with histidine at codon 424 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that the mutant protein to be defective in an ex vivo human cell kinase assay and in one of two in vitro kinase assays (PMID: 31050813) and in two of three yeast complementation assays (PMID 18571837, 22419737, 30851065). This variant has been reported in individuals affected with breast cancer and prostate cancer, but also found in control individuals (PMID: 18085035, 18571837, 22419737, 25186627, 25452441, 31050813). This variant has been identified in 74/281950 chromosomes (63/10344 Ashkenazi Jewish 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590008 SCV000601147 uncertain significance not provided 2019-08-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515214 SCV000611450 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 RCV001175351 SCV000698768 uncertain significance not specified 2019-12-23 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1270T>C (p.Tyr424His) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 250548 control chromosomes (gnomAD). The observed variant frequency is approximately 10-fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Li-Fraumeni Syndrome phenotype (2.8e-05), strongly suggesting that the variant is benign. However, this observation needs to be cautiously considered since the majority of occurrences was detected in the Ashkenazi Jewish subpopulation (a confined population) and additionally, the variant is located in a region of the gene indicated to be affected by pseudogene interference. c.1270T>C has been reported in the literature in individuals affected with cancer, including breast, prostate and colon cancer (e.g. Couch_2015, Kleiblova_2019, Laitman_2007, Roeb_2012, Tischkowitz_2008, Tung_2015). Family studies carried out by some of these studies demonstrated the variant did not segregate with disease (e.g. Roeb_2012, Tischkowitz_2008). Although, functional studies provided conflicting evidence as to whether the variant has a deleterious or benign effect (Delimitsou_2019, Kleiblova_2019, Roeb_2012, Tischkowitz_2008). Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=8) and as likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl RCV000197909 SCV000785377 uncertain significance Familial cancer of breast 2017-07-18 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000590008 SCV000806865 uncertain significance not provided 2020-11-07 criteria provided, single submitter clinical testing
Mendelics RCV000197909 SCV000839462 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001147976 SCV001308836 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355460 SCV001550352 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 p.Tyr424His variant was identified in 6 of 496 proband chromosomes (frequency: 0.0121) from individuals or families with hereditary breast and ovarian cancer (Laitman 2007, Tischkowitz 2008). The variant was also identified in the following databases: dbSNP (ID: rs139366548) as “With Uncertain significance allele”, ClinVar (as uncertain significance by GeneDx, Ambry Genetics, Invitae, Color Genomics, and Quest Diagnostics), and Clinvitae (3x). The variant was not identified in Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 70 of 276482 chromosomes at a frequency of 0.000253 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 3 of 6444 chromosomes (freq: 0.000466), European (Non-Finnish) in 7 of 126180 chromosomes (freq: 0.000055), and Ashkenazi Jewish in 60 of 10128 chromosomes (freq: 0.005924); it was not observed in the African, Latino, East Asian, European (Finnish), and South Asian populations. There are conflicting classifications of this variant in the literature. Roeb (2012) conducted a yeast-based in vivo functional assay and found the variant damaging. They also found that co-segregation of the variant with breast cancer in families is consistent with expectation for damaging alleles of moderate penetrance (Roeb 2012). Another study by Tischkowitz (2008) found the variant occurred in nine affected cases from four different families; however it did not completely segregate with the disease. Functional assays using S. Cerevisae revealed that the p.Tyr424His substitution did not alter function of CHEK2 protein; although the p.Tyr424His variant occurs at a highly conserved position, it does not seem to play a significant role in predisposition to prostate cancer (Tischkowitz 2008). They concluded that while the results do not exclude the possibility that this is a modest-risk predisposition allele in the Ashkenazi Jewish population, functional studies in yeast indicate that the variant does not have a significant deleterious effect (Tischkowitz 2008). The p.Tyr424His residue is conserved in mammals, but not in lower organisms, and the variant amino acid Histidine (His) is present in S. cerevisiae (Brewer’s yeast), increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.
GenomeConnect - Invitae Patient Insights Network RCV001147976 SCV001749496 not provided CHEK2-Related Cancer Susceptibility no assertion provided phenotyping only Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as a Variant of Uncertain Significance by all laboratories and reported most recently on 11/29/2018 by Invitae and 12/22/2014 by GeneDx. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000590008 SCV001807051 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000590008 SCV001906017 uncertain significance not provided no assertion criteria provided clinical testing

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