ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.643C>T (p.Arg215Trp) (rs34767364)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000487932 SCV000604434 likely benign not provided 2017-09-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115802 SCV000184001 likely benign Hereditary cancer-predisposing syndrome 2018-04-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),Subpopulation frequency in support of benign classification,Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene,General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487932 SCV000575564 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
Color RCV000115802 SCV000685805 benign Hereditary cancer-predisposing syndrome 2014-12-12 criteria provided, single submitter clinical testing
Counsyl RCV000007363 SCV000800508 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2017-03-24 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000487932 SCV000231654 uncertain significance not provided 2018-06-07 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115802 SCV000822089 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
GeneReviews RCV000007363 SCV000494626 pathogenic Microcephaly, normal intelligence and immunodeficiency 2017-02-02 no assertion criteria provided literature only
Genetic Services Laboratory, University of Chicago RCV000121621 SCV000595910 uncertain significance not specified 2016-05-05 criteria provided, single submitter clinical testing
ITMI RCV000121621 SCV000085819 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000487932 SCV000697976 uncertain significance not provided 2017-02-02 criteria provided, single submitter clinical testing Variant summary: The NBN c.643C>T (p.Arg215Trp) variant involves the alteration of a non-conserved nucleotide. 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 392/138390 control chromosomes (including 3 homozygotes) at a frequency of 0.0028326, which greater (1.13 time) than the estimated maximal expected allele frequency of a pathogenic NBN variant (0.0025) based on the disease prevalence of NBS (1 in 100000), suggesting this variant is likely a benign polymorphism. However, the frequency in general population is in sub-polymorphic range and these data alone cannot rule out the possibility that it can still have a role as a risk variant in disease. Pathogenic variants in this gene are monogenically linked with NBS (Nijmegen Breakage Syndrome) - an autosomal recessive disorder as well as associated with increased risks for various cancers. The variant has been reported in patients with various cancers such as breast cancer, leukemia, prostate cancer, ovarian cancer, melanoma, colorectal cancer, lung cancer etc. However, it has not been reported to have a considerably significant association with other forms of cancer (Taylor_2003, Hebbring_2006, Bogdanovaas_2008, Dzikiewicz-Krawczyk_2012, and Ramus_2014). This is consistent with studies reporting 95% CI around the OR to include 1.0, thereby providing little to no confidence on the strength of the assertions. Specifically, this variant was not significantly associated with increased risk for breast cancer (Bogdanova_IJC_2008) (adjusted OR = 1.9, 95%CI 0.84.6, p = 0.18) or prostate cancer (Hebbring_Cancer Epidemiol Biomarkers_2006) (OR = 1.24, 95CI 0.31-4.99, p = 0.77). However, from the report by Steffen_2004 and from a meta-analysis (Gao_2013), this variant appears to confer a low but significant risk to cancer. Gao_2013, from the meta-analysis of nine studies that included 6728 cases and 9588 controls, found that OR for cancer was 1.77 (95% CI: 1.072.91, P = 0.025, P het. = 0.641). However, in the stratified analysis of cancer type, no significant risk was observed in breast cancer (carriers vs. non-carriers: OR = 1.44, 95% CI: 0.732.85, P = 0.294, Phet. = 0.357) and the authors concluded that further studies with large sample sizes and tissue-specific histologies are required to confirm their findings. Functional studies in compound heterozygotes with the 675del5 mutation have shown this variant to affect DNA repair and protein stability, however it is difficult from those studies to make conclusions about the effect of NBN Arg215Trp alone (Seemanova 2006, Bogdanova 2008, di Masi 2008, Mendez 2012). It was found in a triple negative breast cancer cell line with alternate molecular basis for disease attributed to BRCA1, p.R715X mutation. Although the tumor specimen showed LOH for this NBN variant, the tumor histological characteristics and sensitivity of the cell line to PARP inhibitors can be attributed to the BRCA1 variant. Therefore, the overall implication of these functional data in causation of the NBS or cancer phenotype needs to be further clarified or is unknown (Schroder-Heurich_BMC Cancer_2014). Meanwhile, functional assays from heterozygous carriers of this variant have also shown the evidences of functional impairment (such as reduced expression of full-length nibrin, impairment in binding with gamma-H2AX and reduction in DNA-DSB rejoining) [Seemanova_2006, di Masi_2006, Dzikiewicz-Krawczyk_2012, and Schroder-Heurich_2014]. From a cell line that also carried BRCA1 p.R1751X, Schroder-Heurich_2014, reports that the (i) cells were highly radiosensitive, susceptible to apoptosis and were deficient in the formation of NBN foci, (ii) NBN was observed only at 30-40% of wildtype levels in the cells; and (iii) there was also evidence for some impairment in the formation of H2AX, MDC1, and 53BP1 foci after irradiation; and these foci appeared smaller and irregular compared with repair foci in wild-type cells, although ATM signaling was largely unaffected. The authors report that these functional consequences related to NBN are not explained by the BRCA1 mutation. This variant has been found in two severely NBS-affected siblings who were compound heterozygous for this variant and 657del5 (Seemanova_2006). This family data coupled with functional recapitulation in compound heterozygote constructs was the primary reason this variant has been reported as a clinically significant variant. Although NBS has childhood onset, penetrance of pathogenic variants in this gene is unknown. Therefore, it is unclear whether three homozygotes reported in ExAC represent non-penetrant cases. Meanwhile, there is also possibility of them representing as subclinical cases or reduced penetrance. Of three clinical labs reporting this variant, one reported it as uncertain significance and two as likely benign/benign, all without evidence for independent evaluation. Taken together, it represents a very low or no significant risk allele for cancer, while its role in causing NBS needs to be further elucidated. Therefore, this variant has been currently classified as Variant of Uncertain Significance-possibly benign.
Invitae RCV000007363 SCV000166524 benign Microcephaly, normal intelligence and immunodeficiency 2018-01-13 criteria provided, single submitter clinical testing
Mendelics RCV000007363 SCV000838311 likely benign Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing
OMIM RCV000007363 SCV000027562 pathogenic Microcephaly, normal intelligence and immunodeficiency 2006-03-01 no assertion criteria provided literature only
PreventionGenetics RCV000487932 SCV000806447 uncertain significance not provided 2016-08-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121621 SCV000601698 uncertain significance not specified 2017-04-24 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000115802 SCV000788081 likely benign Hereditary cancer-predisposing syndrome 2017-09-05 no assertion criteria provided clinical testing

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