Submissions for variant NM_002485.5(NBN):c.1849G>A (p.Glu617Lys)

gnomAD frequency: 0.00002  dbSNP: rs766602873

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219280	SCV000274089	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-15	criteria provided, single submitter	clinical testing	The p.E617K variant (also known as c.1849G>A), located in coding exon 12 of the NBN gene, results from a G to A substitution at nucleotide position 1849. The glutamic acid at codon 617 is replaced by lysine, an amino acid with similar properties. This variant was reported in 0/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly 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.
Invitae	RCV000460678	SCV000553042	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 617 of the NBN protein (p.Glu617Lys). This variant is present in population databases (rs766602873, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 230513). 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.
Mendelics	RCV000460678	SCV000838300	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000219280	SCV001349306	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 617 of the NBN protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/214106 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290554	SCV001478626	uncertain significance	not specified	2021-01-30	criteria provided, single submitter	clinical testing	Variant summary: NBN c.1849G>A (p.Glu617Lys) results in a 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 1.9e-05 in 214106 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1849G>A in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four 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.
Genome-Nilou Lab	RCV000460678	SCV002044531	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469004	SCV004199648	uncertain significance	Aplastic anemia	2023-05-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000460678	SCV002078532	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-08-31	no assertion criteria provided	clinical testing