ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.52C>A (p.Leu18Ile)

gnomAD frequency: 0.00005  dbSNP: rs587781939
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130303 SCV000185153 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-01 criteria provided, single submitter clinical testing The p.L18I variant (also known as c.52C>A), located in coding exon 2 of the NBN gene, results from a C to A substitution at nucleotide position 52. The leucine at codon 18 is replaced by isoleucine, an amino acid with highly similar properties. This variant was identified in an individual from Barbados who was diagnosed with breast cancer at age 39 (George SHL et al. JAMA Netw Open, 2021 Mar;4:e210307). This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000232902 SCV000287476 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2024-07-08 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 18 of the NBN protein (p.Leu18Ile). This variant is present in population databases (rs587781939, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 141689). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
GeneDx RCV001582603 SCV001812948 uncertain significance not provided 2020-02-14 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab RCV000232902 SCV002045295 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2021-11-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323410 SCV004029430 uncertain significance not specified 2023-07-13 criteria provided, single submitter clinical testing Variant summary: NBN c.52C>A (p.Leu18Ile) results in a 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 8e-06 in 251306 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.52C>A has been reported in the literature in a setting of muligene panel testing in an individual affected with breast cancer, without strong evidence for causality (George_2021). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV003467138 SCV004199596 uncertain significance Aplastic anemia 2023-12-17 criteria provided, single submitter clinical testing
Natera, Inc. RCV000232902 SCV002078700 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-07-29 no assertion criteria provided clinical testing

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