ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.505C>T (p.Arg169Cys) (rs182756889)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115796 SCV000186755 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000115796 SCV000685792 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764786 SCV000895930 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000587269 SCV000149705 uncertain significance not provided 2018-07-30 criteria provided, single submitter clinical testing This variant is denoted NBN c.505C>T at the cDNA level, p.Arg169Cys (R169C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been observed in several individuals with breast cancer and in at least one individual with a personal history of a Lynch syndrome-associated cancer and/or polyps (Kim 2015, Maxwell 2015, Yurgelun 2015, Hauke 2018). NBN Arg169Cys was observed at an allele frequency of 0.058% (11/18870) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the BRCT1 domain (Damiola 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether NBN Arg169Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000123218 SCV000475300 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587269 SCV000697971 uncertain significance not provided 2016-04-07 criteria provided, single submitter clinical testing Variant Summary: The NBN c.505C>T variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools predict a neutral outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.008% which does not exceed the maximal expected allele frequency for a pathogenic variant in NBN (0.25%). The variant has been reported in affected individuals in the literature, without strong evidence for causality (i.e. co-occurrence, co-segregation data). Multiple clinical labs have classified the variant as a VUS. Taken together, this variant has been classified as a variant of uncertain significance until additional evidence becomes available.
Invitae RCV000123218 SCV000166523 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 169 of the NBN protein (p.Arg169Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs182756889, ExAC 0.08%). This variant has been reported in individuals affected with breast cancer (PMID: 25503501, 25712764) and in an individual who was tested for Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127873). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The cysteine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
PreventionGenetics RCV000587269 SCV000806443 uncertain significance not provided 2017-03-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587269 SCV000889550 uncertain significance not provided 2018-01-18 criteria provided, single submitter clinical testing

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