ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1124+6G>T (rs375862750)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000127086 SCV000170639 benign not specified 2014-02-05 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 RCV000587851 SCV000254760 likely benign not provided 2019-02-28 criteria provided, single submitter clinical testing
Color RCV000581770 SCV000690639 likely benign Hereditary cancer-predisposing syndrome 2015-10-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000127086 SCV000697937 uncertain significance not specified 2019-05-23 criteria provided, single submitter clinical testing Variant summary: NBN c.1124+6G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 251304 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (0.00012 vs 0.0025), allowing no conclusion about variant significance. c.1124+6G>T has been reported in the literature in individuals affected with breast cancer and colorectal cancer (Tung_2014, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. A co-occurrence with a pathogenic variant has been reported (BRCA1 c.4357+1G>A; LabCorp), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two labs classified the variant as likely benign while two classified as VUS. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant.
Counsyl RCV000199990 SCV000798092 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-02-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000587851 SCV000806408 likely benign not provided 2017-11-20 criteria provided, single submitter clinical testing

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