Submissions for variant NM_002485.5(NBN):c.2060A>C (p.Lys687Thr)

gnomAD frequency: 0.00003  dbSNP: rs186371605

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000709061	SCV000838298	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2018-07-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000709061	SCV000962797	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2023-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 687 of the NBN protein (p.Lys687Thr). This variant is present in population databases (rs186371605, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 490052). 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.
Illumina Laboratory Services, Illumina	RCV000709061	SCV001323123	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.
Genome-Nilou Lab	RCV000709061	SCV002046074	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580181	SCV002725120	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-26	criteria provided, single submitter	clinical testing	The p.K687T variant (also known as c.2060A>C), located in coding exon 13 of the NBN gene, results from an A to C substitution at nucleotide position 2060. The lysine at codon 687 is replaced by threonine, an amino acid with similar properties. This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res. Treat., 2018 Jul;170:189-196). This amino acid position is 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.
Baylor Genetics	RCV004568268	SCV005056121	uncertain significance	Aplastic anemia	2024-03-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056237	SCV005727308	uncertain significance	not specified	2024-11-01	criteria provided, single submitter	clinical testing	Variant summary: NBN c.2060A>C (p.Lys687Thr) results in a non-conservative amino acid change located in the Nibrin, C-terminal domain (IPR013908) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250596 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2060A>C has been reported in the literature in individuals affected with breast and/or ovarian cancer (e.g. Singh_2018, Guindalini_2022). These reports 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: 29470806, 35264596). ClinVar contains an entry for this variant (Variation ID: 490052). Based on the evidence outlined above, the variant was classified as uncertain significance.