ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1262T>C (p.Leu421Ser) (rs104895032)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212745 SCV000149689 uncertain significance not specified 2017-05-15 criteria provided, single submitter clinical testing This variant is denoted NBN c.1262T>C at the cDNA level, p.Leu421Ser (L421S) at the protein level, and results in the change of a Leucine to a Serine (TTG>TCG). This variant has been reported in two individuals with serous ovarian cancer and at least one individual with a personal history of a Lynch syndrome-associated tumor and/or polyps, but was also present in healthy controls (Ramus 2015, Yurgelun 2015). NBN Leu421Ser was also detected in a multi-ethnic exome SNP array study; however, no statistically significant association with breast cancer was identified after multiple comparisons (Haiman 2013). NBN Leu421Ser was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project or 1000 Genomes. Since Leucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NBN Leu421Ser occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether NBN Leu421Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000114875 SCV000166508 benign not provided 2019-03-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115780 SCV000183761 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Illumina Clinical Services Laboratory,Illumina RCV000123203 SCV000475294 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2016-06-14 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515275 SCV000611485 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2017-05-23 criteria provided, single submitter clinical testing
GeneID Lab - Advanced Molecular Diagnostics RCV000115780 SCV000680451 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000114875 SCV000697942 uncertain significance not provided 2016-12-20 criteria provided, single submitter clinical testing Variant summary: The NBN c.1262T>C (p.Leu421Ser) variant causes a missense change involving a non-conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 45/121354 (1/2696), which does not exceed the estimated maximal expected allele frequency for a pathogenic NBN variant of 1/400 (0.0025) for NBS. The variant of interest has been reported in affected individuals with varying phenotypes (Lynch syndrome, Ovarian cancer, BrC, and CVID) via publications with limited information (ie lack of co-occurrence and/or cosegregation). In addition, multiple clinical laboratories cite variant as "uncertain significance." Therefore, taking all available lines of evidence, the variant of interest is classified as a "variant of uncertain significance," until additional information becomes available.
Counsyl RCV000123203 SCV000799755 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-05-03 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000114875 SCV000806410 uncertain significance not provided 2017-09-08 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000757930 SCV000886451 likely benign Familial cancer of breast 2018-05-29 criteria provided, single submitter research The NBN variant designated as NM_002485.4: c.1262T>C (p.Leu421Ser) is classified as likely benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and yields a likelihood ratio of 1.88 to 1 that the allele is causing cancer in the family (Thompson et al, 2003, PMID:2900794, Damiola et al, 2014, PMID:24894818). However, this variant is found in approximately 1 out of 120 individuals of Ashkenazi Jewish ancestry (exac.broadinstitute.org), which is a higher frequency than expected of a pathogenic NBN variant (Kobayashi et al, 2017, PMID:28166811). It is listed in the ClinVar database (Variation ID: 127009) and has been classified as benign by another clinical laboratory. Computer software programs also predict that this variant is likely to be tolerated. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter NBN function or modify cancer risk. A modest (less than 2-fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Color RCV000115780 SCV000910585 likely benign Hereditary cancer-predisposing syndrome 2015-12-11 criteria provided, single submitter clinical testing
Harris Lab, University of Minnesota RCV000114875 SCV000148770 not provided not provided no assertion provided not provided
True Health Diagnostics RCV000115780 SCV000886692 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-28 no assertion criteria provided clinical testing

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