ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1354A>C (p.Thr452Pro) (rs141137543)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131458 SCV000186442 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-17 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000212747 SCV000211450 likely benign not specified 2017-09-12 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000735122 SCV000253386 likely benign not provided 2019-02-28 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212747 SCV000595915 uncertain significance not specified 2017-02-07 criteria provided, single submitter clinical testing
Mendelics RCV000199946 SCV000838303 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000735122 SCV000863322 uncertain significance not provided 2018-09-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212747 SCV000885816 uncertain significance not specified 2019-04-05 criteria provided, single submitter clinical testing
Color RCV000131458 SCV000910678 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212747 SCV000917862 likely benign not specified 2019-06-03 criteria provided, single submitter clinical testing Variant summary: NBN c.1354A>C (p.Thr452Pro) results in a non-conservative amino acid change located in the outside of any known functional domain 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 0.00022 in 251218 control chromosomes, predominantly at a frequency of 0.0026 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 20.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Moreover, the variant was also identified in 22/2559 African American and 1/7325 of European American women who are cancer free at age over 70 in the FLOSSIES database. c.1354A>C has been reported in the literature in individuals affected with Breast cancer, Endometrial cancer and Lynch syndrome (Tung 2016, Ring 2016, Kolli_2018, and Yurgelun 2015). In two of these publications, co-occurrences with a pathogenic variant have been reported (MLH1 c.677G>A, p.Arg226Gln; PALB2 c.3027delT, p.Glu1010Argfs), providing supporting evidence for a benign role in the patient with Lynch Syndrome and breast cancer, respectively (Yurgelun 2015, Kolli_2018). Additionally, an internal sample also carries the variant of interest and MLH1 c.677G>A (pathogenic). A case control study found the variant to occur mainly in the African American cohort, both in breast cancer cases and controls, however sample sizes in each racial/ethnic group were relatively small to establish a clear relationship between the variant and breast cancer risk (Haiman 2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (3 likely benign, 5 VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000735122 SCV001134493 likely benign not provided 2018-10-20 criteria provided, single submitter clinical testing

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