ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.788T>C (p.Phe263Ser) (rs147626427)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656926 SCV000149715 uncertain significance not provided 2018-08-31 criteria provided, single submitter clinical testing This variant is denoted NBN c.788T>C at the cDNA level, p.Phe263Ser (F263S) at the protein level, and results in the change of a Phenylalanine to a Serine (TTT>TCT). This variant was observed in one individual undergoing cancer panel testing due to a personal and/or family history of breast and/or ovarian cancer (Castera 2014), as well as in an individual with a personal history of breast cancer (Tung 2015). This variant was also observed in a multi-ethnic breast cancer case/control study; however, no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). NBN Phe263Ser was observed at an allele frequency of 0.22% (52/24,032) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the BRCT2 domain (Damiola 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NBN Phe263Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115806 SCV000186194 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-09 criteria provided, single submitter clinical testing The p.F263S variant (also known as c.788T>C), located in coding exon 7 of the NBN gene, results from a T to C substitution at nucleotide position 788. The phenylalanine at codon 263 is replaced by serine, an amino acid with highly dissimilar properties. This alteration was reported in a cohort of 708 European patients with hereditary breast and ovarian cancer tested by next generation sequencing for a panel of hereditary breast and ovarian cancer genes and was classified by the investigators as suspected deleterious based on the AGVGD score and the ESP minor allele frequency; however, no functional or segregation data is available (Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22:1305-13). In our clinical cohort, this alteration is frequently seen in conjunction with NBN p.P593A. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000199794 SCV000254780 likely benign Microcephaly, normal intelligence and immunodeficiency 2020-12-06 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212737 SCV000595916 uncertain significance not specified 2016-04-27 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656926 SCV000806452 uncertain significance not provided 2017-07-20 criteria provided, single submitter clinical testing
Mendelics RCV000199794 SCV000838308 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115806 SCV000902826 likely benign Hereditary cancer-predisposing syndrome 2016-06-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656926 SCV001134520 uncertain significance not provided 2019-07-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212737 SCV001363750 likely benign not specified 2019-01-18 criteria provided, single submitter clinical testing Variant summary: NBN c.788T>C (p.Phe263Ser) results in a non-conservative amino acid change located in the Nibrin, second BRCT domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 277060 control chromosomes, predominantly at a frequency of 0.0022 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 17.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.788T>C has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Castera_2014, Haiman_2013, Tung_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.2808_2811delACAA, p.Ala938fsX21), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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