ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.628G>T (p.Val210Phe) (rs61754796)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115801 SCV000185891 likely benign Hereditary cancer-predisposing syndrome 2017-10-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: No disease association in small case-control study,Other data supporting benign classification
Color RCV000115801 SCV000902597 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515300 SCV000611491 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000114880 SCV000149710 uncertain significance not provided 2018-07-12 criteria provided, single submitter clinical testing This variant is denoted NBN c.628G>T at the cDNA level, p.Val210Phe (V210F) at the protein level, and results in the change of a Valine to a Phenylalanine (GTT>TTT). This variant has been observed in multiple individuals with cancer, including breast, ovarian, sporadic melanoma, mesothelioma, and acute lymphoblastic leukemia (Varon 2001, Mosor 2006, Steffen 2006, Meyer 2007, Mateju 2012, Damiola 2014, Ramus 2015, Bueno 2016). NBN Val210Phe has also been observed in apparently healthy controls (Offer 2010, Mateju 2012, Bodian 2014, Ramus 2015) and was observed at an allele frequency of 0.08% (97/126,420) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NBN Val210Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000121622 SCV000248140 uncertain significance not specified 2015-01-30 criteria provided, single submitter clinical testing
Harris Lab, University of Minnesota RCV000114880 SCV000148775 not provided not provided no assertion provided not provided
ITMI RCV000121622 SCV000085820 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000114880 SCV000697975 uncertain significance not provided 2016-08-08 criteria provided, single submitter clinical testing Variant summary: The c.628G>T (p.Val210Phe) in NBN gene is a missense change that involves a non-conserved nucleotide and 2/4 in silico tools predict benign outcome (SNP&GO not captured here due to low reliability index). The variant of interest is located outside of any known functional domain. The variant is present in control dataset of ExAC at a frequency of 0.00048 (65/136632 chrs tested) predominantly in individuals of European descent. This frequency does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.0025). This variant has been observed in several Br/ OvC, ALL and melanoma pts without strong evidence for causality. No functional studies determining the functional impact of this variant have been conducted and published at the time of evaluation. Many reputable databases/clinical laboratories classified this variant as VUS whereas several publications (Ramus, 2015 and Berardinelli, 2013) have classified the variant as non-deleterious rare polymorphism. Additional clinical and functional data are needed to classify this variant with confidence. Taking together, the variant was classified as VUS until more information becomes available.
Invitae RCV000168062 SCV000218716 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2019-01-03 criteria provided, single submitter clinical testing This variant replaces valine with phenylalanine at codon 210 of the NBN protein (p.Val210Phe). The valine residue is weakly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is present in population databases (rs61754796, ExAC 0.08%). This variant has been reported in individuals affected with acute lymphoblastic leukemia (PMID: 16810201, 11325820), melanoma (PMID: 17496786), breast and/or gynecological cancer (PMID: 22491912, 16770759, 29371908, 26315354), as well as unaffected individuals (PMID: 24728327, 26315354, 20805886). ClinVar contains an entry for this variant (Variation ID: 127014). 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.
Mendelics RCV000168062 SCV000838312 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000114880 SCV000806446 uncertain significance not provided 2017-11-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121622 SCV000601697 uncertain significance not specified 2017-01-20 criteria provided, single submitter clinical testing

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