ClinVar Genomic variation as it relates to human health

Variant summary: NBN c.698_701delAACA (p.Lys233SerfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 252006 control chromosomes (gnomAD). The variant, c.698_701delAACA, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and Nijmegen Breakage Syndrome (Varon_1998, Gass_2017, Ramus_2015, Li_2015, Susswein_2016). These data indicate that the variant may be associated with disease. 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as NBS1 698del4; This variant is associated with the following publications: (PMID: 9590180, 26681312, 24072268, 29915322, 31948886, 26315354, 26534844, 23149842, 27038244, 28374160, 28152038, 30043523, 29961768, 29625052, 26689913, 35626031, 34326862, 33804961, 32427313, 29922827, 32885271, 32338768, 28888541, 36451132, 36623239, 15474156)

The c.698_701delAACA pathogenic mutation, located in coding exon 6 of the NBN gene, results from a deletion of 4 nucleotides at nucleotide positions 698 to 701, causing a translational frameshift with a predicted alternate stop codon (p.K233Sfs*5). This alteration was detected in a series of individuals with Nijmegen breakage syndrome (NBS) (Varon R et al. Cell. 1998 May;93:467-76). This alteration has also been reported in a woman with bilateral breast cancer, multiple skin cancers, and a family history of cancer and a male patient with prostate cancer (Gass J et al. Fam. Cancer. 2017 Oct;16:551-553; Wu Y et al. Eur Urol Oncol. 2020 Apr;3(2):224-230). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

NBN: PVS1, PS4:Moderate, PM2:Supporting

This sequence change creates a premature translational stop signal (p.Lys233Serfs*5) in the NBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). This variant is present in population databases (rs587780100, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Nijmegen breakage syndrome (NBS), and breast/ovarian cancer (PMID: 9590180, 15474156, 26315354, 26534844). This variant is also known as 698del4. ClinVar contains an entry for this variant (Variation ID: 127878). For these reasons, this variant has been classified as Pathogenic.

The NBN p.Lys233SerfsX5 variant was identified in 2 of 7792 proband chromosomes (frequency: 0.00026) from individuals or families with hereditary breast and ovarian cancer (Li_2015, Ramus_2015). The variant was also identified in dbSNP (ID: rs587780100) as “With Pathogenic allele”, ClinVar (as pathogenic by GeneDx, Ambry Genetics, University of Chicago, Invitae, Color Genomics, OMIM and GeneReviews), Clinvitae (3x as in ClinVar), LOVD 3.0, and Zhejiang Colon Cancer Database. The variant was not identified in Cosmic database. The variant was identified in control databases in 5 of 245144 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 15226 chromosomes (freq: 0.000066), European (Non-Finnish) in 4 of 111062 chromosomes (freq: 0.000036), but it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Latino, Other, and South Asian populations. The variant has been reported in families with Nijmegen Breakage Syndrome as well as in individuals with hereditary breast and ovarian cancer (HBOC), and is reported as a variant of English origin (Cybulski_2013, Meyer_2004, Varon_1998). The p.Lys233SerfsX5 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 233 and leads to a premature stop codon at position 237. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the NBN gene are an established mechanism of disease in HBOC and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

The NBN c.698_701delAACA variant is predicted to result in a frameshift and premature protein termination (p.Lys233Serfs*5). This variant has been reported in a patient with Nijmemgen breakage syndrome (Varon et al. 1998. PubMed ID: 9590180) and in individuals with various cancers, including breast and skin, prostate, or ovarian cancers (for example, Gass et al. 2017. PubMed ID: 28374160; Supplementary Table, Lerner-Ellis. 2020. PubMed ID: 32885271; Table S7, Lilyquist. 2017. PubMed ID: 28888541). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD, and has been interpreted as pathogenic in ClinVar. Frameshift variants in NBN are expected to be pathogenic. This variant is interpreted as pathogenic.