ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1729G>T (p.Asp577Tyr) (rs587781881)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130210 SCV000185048 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000199051 SCV000254768 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 577 of the NBN protein (p.Asp577Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs587781881, ExAC 0.004%). This variant has been reported in an individual affected with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 141617). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genetic Services Laboratory, University of Chicago RCV000499428 SCV000595918 uncertain significance not specified 2017-03-08 criteria provided, single submitter clinical testing
Color RCV000130210 SCV000685734 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589088 SCV000697952 uncertain significance not provided 2017-06-09 criteria provided, single submitter clinical testing Variant summary: The NBN c.1729G>T (p.Asp577Tyr) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant was found in 3/121386 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic NBN variant (0.0025). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. A publication cites the variant in an affected individual diagnosed with early-onset colorectal cancer with limited information (ie, lack of cosegregation data). Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589088 SCV000888328 uncertain significance not provided 2017-12-20 criteria provided, single submitter clinical testing

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