ClinVar Genomic variation as it relates to human health

Variant summary: NBN c.1667T>A (p.Val556Glu) results in a non-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 2e-05 in 251204 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1667T>A has been reported in the literature in individuals affected with epithelial ovarian cancer and breast cancer (Ramus_2015, Hauke_2018), however it was also found in 1/7325 European American women, older than age 70 years who have never had cancer (in the FLOSSIES database). These reports 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. Six 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.

The frequency of this variant in the general population, 0.000044 (5/113546 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. This variant was also reported in one cancer-free woman over 70 years old (FLOSSIES, https://whi.color.com/). In the published literature, the variant has been reported in individuals with ovarian cancer (PMID: 26315354 (2015)) and in individuals with breast cancer (PMID: 29522266 (2018)). It has also been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/NBN)). 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.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26315354, 32885271, 33471991, 34326862, 38446568, 29522266, 36346689)

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 556 of the NBN protein (p.Val556Glu). This variant is present in population databases (rs558023830, gnomAD 0.004%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26315354, 29522266). ClinVar contains an entry for this variant (Variation ID: 127859). 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.

The p.V556E variant (also known as c.1667T>A), located in coding exon 11 of the NBN gene, results from a T to A substitution at nucleotide position 1667. The valine at codon 556 is replaced by glutamic acid, an amino acid with dissimilar properties. In one study, this alteration was observed in 3/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst., 2015 Nov;107:). It was also detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358) and in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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.

The NBN p.Val556Glu variant was identified in 4 of 17650 proband chromosomes (frequency: 0.0002) from American, Australian, British and German individuals or families with breast or ovarian cancer and was not identified in 6862 control chromosomes from healthy individuals (Ramus 2015, Hauke 2018). The variant was identified in dbSNP (ID: rs558023830) as “With Uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and 2 other submitters). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 5 of 245964 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), in the European Non-Finnish population in 5 of 111478 chromosomes (freq: 0.00005); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Val556 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Glu variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.