ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587269 SCV000149705 uncertain significance not provided 2021-01-19 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer or a Lynch syndrome-associated cancer, but also in healthy controls (Kim 2015, Maxwell 2015, Yurgelun 2015, Hauke 2018, Fujita 2020); This variant is associated with the following publications: (PMID: 25712764, 25980754, 25503501, 29522266, 33309985)
Invitae RCV000123218 SCV000166523 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2019-11-26 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.
Ambry Genetics RCV000115796 SCV000186755 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-07 criteria provided, single submitter clinical testing The p.R169C variant (also known as c.505C>T), located in coding exon 5 of the NBN gene, results from a C to T substitution at nucleotide position 505. The arginine at codon 169 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple BRCA1 and BRCA2-negative breast cancer patient cohorts (Maxwell KN et al. Genet. Med., 2015 Aug;17:630-8; Kim H et al. Fam. Cancer, 2015 Sep;14:365-71; Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This amino acid position is not 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.
Illumina Clinical Services Laboratory,Illumina RCV000123218 SCV000475300 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Health, Inc RCV000115796 SCV000685792 likely benign Hereditary cancer-predisposing syndrome 2020-03-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001549273 SCV000697971 uncertain significance not specified 2021-07-12 criteria provided, single submitter clinical testing Variant summary: NBN c.505C>T (p.Arg169Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 298708 control chromosomes (gnomAD and Momozawa_2018. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.00013), strongly suggesting that the variant is benign. c.505C>T has been reported in the literature in individuals affected with various types of cancers including but not limiting to breast and/or ovarian cancer, colorectal cancer, nasopharyngeal cancer and gall bladder cancer (example: Fujita_2020, Kwong_2020, Momozawa_2018, Terashima_2019, Wang_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=9) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics,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
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
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030567 SCV001193657 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Natera, Inc. RCV000123218 SCV001461772 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-09-16 no assertion criteria provided clinical testing

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