ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.595C>T (p.Pro199Ser) (rs587780097)

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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 RCV000115798 SCV000215098 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115798 SCV000910803 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
Counsyl RCV000461206 SCV000788765 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2017-01-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515203 SCV000611490 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000235189 SCV000149707 uncertain significance not provided 2018-10-31 criteria provided, single submitter clinical testing This variant is denoted NBN c.595C>T at the cDNA level, p.Pro199Ser (P199S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). This variant has been observed in individuals with a personal history of breast cancer (Mateju 2012, Kraus 2017, Hauke 2018). NBN Pro199Ser was observed at an allele frequency of 0.04% (4/9,836) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located within the BRCT1 domain (Damiola 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether NBN Pro199Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000461206 SCV000553036 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 199 of the NBN protein (p.Pro199Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs587780097, ExAC 0.005%). This variant has been reported in individuals affected with breast cancer (PMID: 22491912, 27616075). ClinVar contains an entry for this variant (Variation ID: 127874). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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.

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