Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000230649 | SCV000287444 | uncertain significance | Microcephaly, normal intelligence and immunodeficiency | 2024-01-19 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 341 of the NBN protein (p.Ser341Arg). This variant is present in population databases (rs756023239, gnomAD 0.07%). This missense change has been observed in individual(s) with NBN-related cancer (PMID: 32068069, 36346689). ClinVar contains an entry for this variant (Variation ID: 239182). 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 tolerated. 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. |
Illumina Laboratory Services, |
RCV000230649 | SCV000475297 | uncertain significance | Microcephaly, normal intelligence and immunodeficiency | 2018-01-13 | 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. |
Ambry Genetics | RCV000446226 | SCV000662710 | likely benign | Hereditary cancer-predisposing syndrome | 2023-01-26 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Gene |
RCV001770195 | SCV001992453 | uncertain significance | not provided | 2022-09-12 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in controls but absent from cases in a case-control study of breast cancer (Momozawa 2018); This variant is associated with the following publications: (PMID: 30287823) |
Genome- |
RCV000230649 | SCV002045942 | uncertain significance | Microcephaly, normal intelligence and immunodeficiency | 2021-11-07 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV001818596 | SCV002068681 | uncertain significance | not specified | 2019-03-04 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001818596 | SCV004122063 | uncertain significance | not specified | 2023-10-24 | criteria provided, single submitter | clinical testing | Variant summary: NBN c.1023C>G (p.Ser341Arg) results in a non-conservative amino acid change in 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 5e-05 in 262613 control chromosomes. c.1023C>G has been reported in the literature in individuals affected with breast cancer, epithelial ovarian cancer, or other unspecified cancer, without evidence of causality (e.g. Kwong_2020, Belhadj_2022, Yao_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36346689, 32068069, 30287823, 35186721). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. |
Baylor Genetics | RCV003469157 | SCV004199704 | uncertain significance | Aplastic anemia | 2022-12-06 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001770195 | SCV004222110 | uncertain significance | not provided | 2023-07-12 | criteria provided, single submitter | clinical testing | In the published literature, this variant has been reported in individuals with breast cancer as well as unaffected individuals (PMID: 30287823 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/NBN)). The frequency of this variant in the general population, 0.0007 (14/19954 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. |
Natera, |
RCV000230649 | SCV001460724 | uncertain significance | Microcephaly, normal intelligence and immunodeficiency | 2020-09-16 | no assertion criteria provided | clinical testing |