Submissions for variant NM_002485.5(NBN):c.1667T>A (p.Val556Glu)

gnomAD frequency: 0.00006  dbSNP: rs558023830

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212748	SCV000149691	uncertain significance	not provided	2025-02-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26315354, 32885271, 33471991, 34326862, 38446568, 29522266, 36346689)
Ambry Genetics	RCV000115782	SCV000186599	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-08	criteria provided, single submitter	clinical testing	The p.V556E variant (also known as c.1667T>A), located in coding exon 11 of the NBN gene, results from a T to A substitution at nucleotide position 1667. The valine at codon 556 is replaced by glutamic acid, an amino acid with dissimilar properties. In one study, this alteration was observed in 3/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst., 2015 Nov;107:). It was also detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358) and in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is poorly 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	RCV000459014	SCV000553056	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2024-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 556 of the NBN protein (p.Val556Glu). This variant is present in population databases (rs558023830, gnomAD 0.004%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26315354, 29522266, 34326862). ClinVar contains an entry for this variant (Variation ID: 127859). 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.
PreventionGenetics, part of Exact Sciences	RCV000212748	SCV000806414	uncertain significance	not provided	2017-12-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328384	SCV001519507	uncertain significance	not specified	2021-03-01	criteria provided, single submitter	clinical testing	Variant summary: NBN c.1667T>A (p.Val556Glu) 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 2e-05 in 251204 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1667T>A has been reported in the literature in individuals affected with epithelial ovarian cancer and breast cancer (Ramus_2015, Hauke_2018), however it was also found in 1/7325 European American women, older than age 70 years who have never had cancer (in the FLOSSIES database). These reports 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212748	SCV002011227	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000459014	SCV002044575	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212748	SCV004222122	uncertain significance	not provided	2023-01-19	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000044 (5/113546 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. This variant was also reported in one cancer-free woman over 70 years old (FLOSSIES, https://whi.color.com/). In the published literature, the variant has been reported in individuals with ovarian cancer (PMID: 26315354 (2015)) and in individuals with breast cancer (PMID: 29522266 (2018)). It has also been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/NBN)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV004567018	SCV005056143	uncertain significance	Aplastic anemia	2024-02-20	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000459014	SCV005689159	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2024-09-18	criteria provided, single submitter	clinical testing	The NBN c.1667T>A (p.Val556Glu) missense change has a maximum subpopulation frequency of 0.004% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Nijmegan breakage syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Natera, Inc.	RCV000459014	SCV001456594	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356139	SCV001551213	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN p.Val556Glu variant was identified in 4 of 17650 proband chromosomes (frequency: 0.0002) from American, Australian, British and German individuals or families with breast or ovarian cancer and was not identified in 6862 control chromosomes from healthy individuals (Ramus 2015, Hauke 2018). The variant was identified in dbSNP (ID: rs558023830) as “With Uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and 2 other submitters). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 5 of 245964 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), in the European Non-Finnish population in 5 of 111478 chromosomes (freq: 0.00005); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Val556 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Glu variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.