ClinVar Genomic variation as it relates to human health

Variant summary: NBN c.633T>A (p.Asp211Glu) results in a conservative amino acid change in 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 3.2e-05 in 250928 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.633T>A has been reported in the literature in individuals with a personal and/or family history of breast and/or ovarian cancer, as well as unaffected controls (e.g. Ramus_2015, Tsaousis_2019, Dorling_2021, Krivokuca_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: 33471991, 26315354, 31159747, 34284872, 36346689). ClinVar contains an entry for this variant (Variation ID: 140805). Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 211 of the NBN protein (p.Asp211Glu). This variant is present in population databases (rs377700348, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of NBN-related conditions (PMID: 26315354, 31159747). ClinVar contains an entry for this variant (Variation ID: 140805). 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.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or ovarian cancer (Ramus et al., 2015; Hauke et al., 2018; Krivokuca et al., 2019); This variant is associated with the following publications: (PMID: 26315354, 26257771, 28497333, 31159747, 29522266, 28801450, 30651582)

The p.D211E variant (also known as c.633T>A), located in coding exon 6 of the NBN gene, results from a T to A substitution at nucleotide position 633. The aspartic acid at codon 211 is replaced by glutamic acid, an amino acid with highly similar properties. In one study, this alteration was observed in 1/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107:). This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This alteration was also identified in a cohort of 131 women diagnosed with epithelial ovarian cancer in Serbia (Krivokuca A et al. J Hum Genet, 2019 Apr;64:281-290) and in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome who underwent expanded Breast and Ovarian Cancer Panel testing (Lerner-Ellis J et al. J Cancer Res Clin Oncol 2021 Mar;147(3):871-879). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The NBN p.Asp211Glu variant was identified in 2 of 6488 proband chromosomes (frequency: 0.0003) from individuals or families with ovarian cancer and was not identified in 6862 control chromosomes from healthy individuals (Balendran 2017, Ramus 2015). The variant was also identified in dbSNP (ID: rs377700348) as “With Uncertain significance allele”, ClinVar (as uncertain significance by Ambry Genetics, Invitae, GeneDx, and three other submitters). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 9 of 276778 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6452 chromosomes (freq: 0.0002), Latino in 1 of 34354 chromosomes (freq: 0.00003), and European in 7 of 126420 chromosomes (freq: 0.00006), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asp211 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.