Submissions for variant NM_002485.5(NBN):c.1382C>T (p.Pro461Leu)

gnomAD frequency: 0.00007  dbSNP: rs367760321

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000539528	SCV000634224	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 461 of the NBN protein (p.Pro461Leu). This variant is present in population databases (rs367760321, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 461508). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV000567288	SCV000666504	likely benign	Hereditary cancer-predisposing syndrome	2023-04-03	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.
GeneDx	RCV001591216	SCV001823629	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Tung et al., 2015); This variant is associated with the following publications: (PMID: 25186627, 34204722, 24894818, 33471991)
Genome-Nilou Lab	RCV000539528	SCV002044642	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821527	SCV002067249	uncertain significance	not specified	2021-07-29	criteria provided, single submitter	clinical testing	DNA sequence analysis of the NBN gene demonstrated a sequence change, c.1382C>T, in exon 10 that results in an amino acid change, p.Pro461Leu. This sequence change has been described in the gnomAD database with a frequency of 0.032% in the African/African-American subpopulation (dbSNP rs367760321). The p.Pro461Leu change affects a moderately conserved amino acid residue located in a domain of the NBN protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro461Leu substitution. This sequence change does not appear to have been previously described in individuals with NBN-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro461Leu change remains unknown at this time.
Sema4, Sema4	RCV000567288	SCV002536594	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-15	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821527	SCV002548242	uncertain significance	not specified	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: NBN c.1382C>T (p.Pro461Leu) results in a non-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 3.2e-05 in 251072 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1382C>T has been reported in the literature as a VUS in settings of multigene panel testing among individuals with breast cancer (example, Tung_2015, Fonfria_2021). 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. Seven 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.
PreventionGenetics, part of Exact Sciences	RCV003419937	SCV004116871	uncertain significance	NBN-related disorder	2023-06-13	criteria provided, single submitter	clinical testing	The NBN c.1382C>T variant is predicted to result in the amino acid substitution p.Pro461Leu. This variant has been reported in an individual with breast cancer (Tung et al. 2015. PubMed ID: 25186627). This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-90967526-G-A) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/461508/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003476251	SCV004199546	uncertain significance	Aplastic anemia	2024-01-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001591216	SCV004222118	uncertain significance	not provided	2022-11-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00032 (8/24904 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 25186627 (2015), 34204722 (2021), and 33471991 (2021); see also LOVD (http://databases.lovd.nl/shared/)). In addition, this variant has been reported in elderly cancer free women (Flossies, (https://whi.color.com/)). 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.
Natera, Inc.	RCV000539528	SCV001466978	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-07-05	no assertion criteria provided	clinical testing