Submissions for variant NM_002485.5(NBN):c.644G>A (p.Arg215Gln)

gnomAD frequency: 0.00001  dbSNP: rs61753718

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130586	SCV000185459	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-29	criteria provided, single submitter	clinical testing	The p.R215Q variant (also known as c.644G>A), located in coding exon 6 of the NBN gene, results from a G to A substitution at nucleotide position 644. The arginine at codon 215 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in 4/60,466 breast cancer cases and in 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well 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.
GeneDx	RCV000587953	SCV000279506	uncertain significance	not provided	2023-05-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in cases and controls in a breast cancer study (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 31278556, 33471991)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461583	SCV000553071	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 215 of the NBN protein (p.Arg215Gln). This variant is present in population databases (rs61753718, 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: 141888). 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 disruptive. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818316	SCV000697977	uncertain significance	not specified	2024-09-09	criteria provided, single submitter	clinical testing	Variant summary: NBN c.644G>A (p.Arg215Gln) 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 2.4e-05 in 250882 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.644G>A has been reported in the literature in a cohort of individuals with increased risk of cancer (Belhadj_2023). 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 publication has been ascertained in the context of this evaluation (PMID: 36346689). ClinVar contains an entry for this variant (Variation ID: 141888). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000461583	SCV000799005	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2018-04-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587953	SCV001134516	uncertain significance	not provided	2019-03-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000461583	SCV002044828	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818316	SCV002071732	uncertain significance	not specified	2020-03-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the NBN gene demonstrated a sequence change, c.644G>A, in exon 6 that results in an amino acid change, p.Arg215Gln. This sequence change does not appear to have been previously described in patients with NBN-related disorders and has been described in the gnomAD database with a low population frequency of 0.0047% in the non-Finnish European subpopulation (dbSNP rs61753718). The p.Arg215Gln change affects a moderatel conserved amino acid residue located in a domain of the NBN protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg215Gln substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg215Gln change remains unknown at this time.
Sema4, Sema4	RCV000130586	SCV002536701	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-05	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000461583	SCV002584715	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2022-10-07	criteria provided, single submitter	clinical testing	The NBN c.644G>A (p.Arg215Gln) missense change has a maximum subpopulation frequency of 0.0047% 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. This variant has been reported in a large case-control study of breast cancer in 4 of 60,466 cases and 5 of 53,461 controls (PMID: 33471991). 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.
Revvity Omics, Revvity	RCV000587953	SCV003813486	uncertain significance	not provided	2022-03-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467148	SCV004199526	uncertain significance	Aplastic anemia	2024-02-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000461583	SCV001460734	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-09-16	no assertion criteria provided	clinical testing