ClinVar Miner

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

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587890 SCV000149905 uncertain significance not provided 2018-10-04 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1312G>T at the cDNA level, p.Asp438Tyr (D438Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAT>TAT). This variant, also denoted c.1441G>T and p.Asp481Tyr using an alternate reference sequence (NP_001005735.1), has been observed in individuals with a history of breast, prostate, colorectal, or endometrial cancer, as well as in healthy controls (Seppala 2003, Bell 2007, Tischkowitz 2008, Le Calvez-Kelm 2011, Baloch 2014, Tung 2015, Ring 2016, Kayser 2018). No statistically significant association with breast cancer has been identified; however, evidence of a weak association with prostate cancer has been reported (Southey 2016). CHEK2 Asp438Tyr was shown to exhibit a 70% reduction in kinase activity in a cell-based assay when compared to wild-type CHEK2 (Bell 2007). However, it is unclear whether such a reduction in kinase activity would be sufficient to contribute to cancer risk. Although this variant was observed in large population cohorts, population data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). CHEK2 Asp438Tyr is located within the protein 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, it is unclear whether CHEK2 Asp438Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115996 SCV000172942 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000199565 SCV000254923 likely benign Familial cancer of breast 2019-12-31 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 RCV000115996 SCV000537526 likely benign Hereditary cancer-predisposing syndrome 2019-08-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000200982 SCV000601150 uncertain significance not specified 2017-05-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515311 SCV000611451 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000200982 SCV000698770 uncertain significance not specified 2019-05-06 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 0.00039 in 259462 control chromosomes, predominantly at a frequency of 0.0013 within the Finnish European subpopulation in the gnomAD database. The observed variant frequency within Finnish European control individuals in the gnomAD database is approximately 4 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. 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 overlapping pseudogenes. The variant, 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 (Baloch_2013, Bell_2007, LeCalvez-Kelm_2011, Seppala_2003, Tischkowitz_2008, Young_2016, Yadav_2016, Maxwell_2016). 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. Eleven other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (10x) or likely benign (1x). 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.
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.

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