Submissions for variant NM_002485.5(NBN):c.786C>A (p.Phe262Leu)

gnomAD frequency: 0.00021  dbSNP: rs372159380

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165014	SCV000215709	likely benign	Hereditary cancer-predisposing syndrome	2022-04-19	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	RCV000214639	SCV000279303	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with colon cancer (Pearlman et al., 2017); This variant is associated with the following publications: (PMID: 24894818, 27978560)
Invitae	RCV000473725	SCV000553118	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 262 of the NBN protein (p.Phe262Leu). This variant is present in population databases (rs372159380, gnomAD 0.05%). This missense change has been observed in individual(s) with colon cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 185571). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000214639	SCV001134519	uncertain significance	not provided	2023-01-13	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00044 (11/24962 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 27978560 (2016)). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264536	SCV001442740	uncertain significance	not specified	2022-02-10	criteria provided, single submitter	clinical testing	Variant summary: NBN c.786C>A (p.Phe262Leu) results in a non-conservative amino acid change located in the Nibrin, second BRCT domain (IPR032429) of 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 3.6e-05 in 251270 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.786C>A has been reported in the literature in at-least one individual affected with early-onset MMR tumor status: Proficient, colorectal cancer (Pearlman_2017). This report does 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 ClinVar submitters have assessed the variant since 2014: all classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000473725	SCV002044790	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165014	SCV002536715	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-10	criteria provided, single submitter	curation
Baylor Genetics	RCV003462161	SCV004199493	uncertain significance	Aplastic anemia	2024-03-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000473725	SCV002078632	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-02-19	no assertion criteria provided	clinical testing