ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.425A>G (p.Asn142Ser) (rs769414)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115794 SCV000186535 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115794 SCV000910599 likely benign Hereditary cancer-predisposing syndrome 2016-01-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515292 SCV000611488 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000121617 SCV000149703 likely benign not specified 2018-01-29 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.
Genetic Services Laboratory, University of Chicago RCV000121617 SCV000248138 uncertain significance not specified 2015-06-17 criteria provided, single submitter clinical testing
ITMI RCV000121617 SCV000085815 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000121617 SCV000697969 likely benign not specified 2018-11-12 criteria provided, single submitter clinical testing Variant summary: NBN c.425A>G (p.Asn142Ser) results in a conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 284406 control chromosomes (gnomAD and publications). The observed variant frequency is approximately 1.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), suggesting that the variant might be benign. The variant, c.425A>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Ramus_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other 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 (likely benign x2, VUS x6). Our laboratory classified this variant as a "VUS-possibly normal" in October-2016, however, no new evidence supporting pathogenicity have been reported and at-least two other testing laboratories have classified this variant as likely benign since our original classification. Therefore, the overall evidence seems to be shifting from uncertain significance to likely benign consistent with a variant frequency in unaffected much higher than expected from disease prevalence. Based on the evidence outlined above, until more clinical and functional data become available, the variant was classified as likely benign.
Invitae RCV000168260 SCV000218931 likely benign Microcephaly, normal intelligence and immunodeficiency 2017-12-27 criteria provided, single submitter clinical testing
Mendelics RCV000168260 SCV000838315 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000589414 SCV000806440 uncertain significance not provided 2017-06-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121617 SCV000601693 uncertain significance not specified 2017-02-04 criteria provided, single submitter clinical testing

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