Submissions for variant NM_002485.5(NBN):c.1925A>G (p.Lys642Arg)

gnomAD frequency: 0.00002  dbSNP: rs587781547

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129561	SCV000184343	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-19	criteria provided, single submitter	clinical testing	The p.K642R variant (also known as c.1925A>G), located in coding exon 13 of the NBN gene, results from an A to G substitution at nucleotide position 1925. The lysine at codon 642 is replaced by arginine, an amino acid with highly similar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med. 2018 04;7:1349-1358). 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	RCV000204812	SCV000260089	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 642 of the NBN protein (p.Lys642Arg). This variant is present in population databases (rs587781547, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of NBN-related conditions (PMID: 29522266). ClinVar contains an entry for this variant (Variation ID: 141169). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Illumina Laboratory Services, Illumina	RCV000204812	SCV000475289	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780524	SCV000917854	uncertain significance	not specified	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: NBN c.1925A>G (p.Lys642Arg) results in a conservative amino acid change in the encoded protein sequence. Five 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 251052 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1925A>G has been reported in the literature in individuals from cancer cohort studies without strong evidence for causality (examples: Bova_2016, Belhadj_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36346689, 27148588). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000204812	SCV002044510	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917419	SCV004734478	uncertain significance	NBN-related disorder	2024-02-20	criteria provided, single submitter	clinical testing	The NBN c.1925A>G variant is predicted to result in the amino acid substitution p.Lys642Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD and is listed in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/141169/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, University of Tampere	RCV000206550	SCV000259016	uncertain significance	Malignant tumor of prostate		no assertion criteria provided	research
Natera, Inc.	RCV000204812	SCV002078524	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-11-20	no assertion criteria provided	clinical testing