Submissions for variant NM_002485.5(NBN):c.1262T>C (p.Leu421Ser)

gnomAD frequency: 0.00027  dbSNP: rs104895032

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000114875	SCV000149689	likely benign	not provided	2021-05-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25980754, 26315354, 23555315, 20805886, 28135145, 28873162, 28726808, 30374176, 31278556)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123203	SCV000166508	benign	Microcephaly, normal intelligence and immunodeficiency	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115780	SCV000183761	likely benign	Hereditary cancer-predisposing syndrome	2019-03-21	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.
Illumina Laboratory Services, Illumina	RCV000123203	SCV000475294	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.
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212745	SCV000697942	likely benign	not specified	2024-09-05	criteria provided, single submitter	clinical testing	Variant summary: NBN c.1262T>C (p.Leu421Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 260122 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (0.00037 vs 0.0025), allowing no conclusion about variant significance. The variant was also reported in 7 European American women older than age 70 years who have never had cancer. This data provide supporting evidence for a benign role. c.1262T>C has been reported in the literature in individuals affected with CVID, OvC, HBOC, Lynch syndrome and PDAC (e.g. Offer_2010, Ramus_2015, Tung_2015, Yurgelun_2015, 2017, Chaffee_2018, Dorling_2021) but it was also reported in multiple controls (Offer_2010, Ramus_2015, Dorling_2021). Additionally, evidence of non co-segregation with disease was provided through the study of a large family affected with different types of cancer including breast cancer (Tsai_2019), providing further supporting evidence for a benign role. 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: 34326862, 28726808, 33471991, 23555315, 20805886, 26315354, 30374176, 25186627, 25980754, 28135145, 35534704). ClinVar contains an entry for this variant (Variation ID: 127009). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000123203	SCV000799755	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2018-05-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	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.
Mendelics	RCV000123203	SCV001137663	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2019-05-28	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000114875	SCV002011228	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000123203	SCV002045927	likely benign	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000114875	SCV002046113	likely benign	not provided	2023-01-12	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212745	SCV002071521	likely benign	not specified	2021-12-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115780	SCV002536582	benign	Hereditary cancer-predisposing syndrome	2021-02-13	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115780	SCV002819156	likely benign	Hereditary cancer-predisposing syndrome	2023-01-10	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
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358304	SCV001554001	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN p.Leu421Ser variant was identified in 5 of 11992 proband chromosomes (frequency: 0.0004) from individuals or families with antibody deficiency syndromes IgAD or CVID, ovarian cancer or Lynch syndrome and was present in 3 of 8746 control chromosomes (frequency: 0.0005) from healthy individuals (Offer 2010, Ramus 2015, Yurgelun 2015, Yurgelun 2017). The variant was also found in Genome-Wide testing of putative functional exonic variants with relative risk 1.224 and P=0.87 (Haiman 2013). The variant was identified in dbSNP (ID: rs104895032) as "With other allele", and in ClinVar (classified as benign by Invitae; as uncertain significance by eight submitters). The variant was not identified in LOVD 3.0 database. The variant was identified in control databases in 105 of 277090 chromosomes (1 homozygous) at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 6 of 24016 chromosomes (freq: 0.0003), Other in 3 of 6458 chromosomes (freq: 0.0005), Latino in 1 of 34408 chromosomes (freq: 0.00003), European in 44 of 126620 chromosomes (freq: 0.0004), Ashkenazi Jewish in 43 of 10152 chromosomes (freq: 0.004), Finnish in 8 of 25790 chromosomes (freq: 0.0003), while the variant was not observed in the East Asian, and South Asian populations. The p.Leu421 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000114875	SCV001797367	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000114875	SCV001966880	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000114875	SCV001978103	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000123203	SCV002078588	benign	Microcephaly, normal intelligence and immunodeficiency	2019-11-11	no assertion criteria provided	clinical testing