ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.628G>T (p.Val210Phe) (rs61754796)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000115801 SCV000185891 likely benign Hereditary cancer-predisposing syndrome 2018-10-09 criteria provided, single submitter clinical testing No disease association in small case-control study;Other data supporting benign classification
Invitae RCV000168062 SCV000218716 likely benign Microcephaly, normal intelligence and immunodeficiency 2020-01-06 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000121622 SCV000248140 uncertain significance not specified 2015-01-30 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
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
Integrated Genetics/Laboratory Corporation of America RCV000121622 SCV000697975 uncertain significance not specified 2019-07-22 criteria provided, single submitter clinical testing Variant summary: NBN c.628G>T (p.Val210Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 267128 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (0.0004 vs 0.0025), allowing no conclusion about variant significance. c.628G>T has been reported in the literature in individuals affected with HBOC, ALL, and melanoma; however, these reports do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (7x) and twice as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics,PreventionGenetics RCV000114880 SCV000806446 uncertain significance not provided 2017-11-15 criteria provided, single submitter clinical testing
Mendelics RCV000168062 SCV000838312 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000115801 SCV000902597 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000114880 SCV001155448 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000121622 SCV001157433 uncertain significance not specified 2019-03-25 criteria provided, single submitter clinical testing The NBN c.628G>T; p.Val210Phe variant (rs61754796) is reported in the literature in individuals with melanoma, acute lymphoblastic leukemia, breast or ovarian cancer (Dominguez-Valentin 2018, Mateju 2012, Meyer 2007, Mosor 2006, Ramus 2015, Steffen 2006, Varon 2001), but is also reported in controls (Mateju 2012, Offer 2010, Ramus 2015). This variant is also found in the general population with an overall allele frequency of 0.04% (115/282316 alleles) in the Genome Aggregation Database. This variant is classified as uncertain by multiple laboratories in ClinVar (Variation ID: 127014). The valine at codon 210 is weakly conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Based on available information, the clinical significance of this variant is uncertain at this time. REFERENCES Dominguez-Valentin M et al. Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds. Hered Cancer Clin Pract. 2018 Jan 15;16:4. Mateju M et al. Germline mutations 657del5 and 643C>T (R215W) in NBN are not likely to be associated with increased risk of breast cancer in Czech women. Breast Cancer Res Treat. 2012 Jun;133(2):809-11. Meyer P et al. Molecular genetic analysis of NBS1 in German melanoma patients. Melanoma Res. 2007 Apr;17(2):109-16. Mosor M et al. Association of the heterozygous germline I171V mutation of the NBS1 gene with childhood acute lymphoblastic leukemia. Leukemia. 2006 Aug;20(8):1454-6. Offer SM et al. Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID. PLoS One. 2010 Aug 18;5(8):e12260. Ramus SJ et al. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J Natl Cancer Inst. 2015 Aug 27;107(11). Steffen J et al. Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland. Int J Cancer. 2006 Jul 15;119(2):472-5. Varon R et al. Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL). Cancer Res. 2001 May 1;61(9):3570-2.
Illumina Clinical Services Laboratory,Illumina RCV000168062 SCV001323246 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2017-08-29 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ITMI RCV000121622 SCV000085820 not provided not specified 2013-09-19 no assertion provided reference population
Harris Lab, University of Minnesota RCV000114880 SCV000148775 not provided not provided no assertion provided not provided

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