Submissions for variant NM_002485.5(NBN):c.2117C>G (p.Ser706Ter)

gnomAD frequency: 0.00001  dbSNP: rs730881857

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212754	SCV000211460	likely pathogenic	not provided	2024-03-08	criteria provided, single submitter	clinical testing	Nonsense 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); Observed in individuals with a personal and/or family history of breast, prostate, and other cancers (PMID: 26681312, 22864661, 29625052); This variant is associated with the following publications: (PMID: 23149842, 26681312, 22864661, 32875559, 29625052, 30590007, 33077847, 35434237, Mendhiratta2023[abstract], 29922827, 36451132, 33047316, 36495689)
Ambry Genetics	RCV000160795	SCV000217454	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-06	criteria provided, single submitter	clinical testing	The p.S706* pathogenic mutation (also known as c.2117C>G), located in coding exon 14 of the NBN gene, results from a C to G substitution at nucleotide position 2117. This changes the amino acid from a serine to a stop codon within coding exon 14. This mutation has previously been reported in a family with hereditary prostate cancer (Zuhlke KA et al. Fam. Cancer. 2012 Dec;11:595-600) and in an individual with a personal history of breast cancer (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). 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.
Counsyl	RCV000409031	SCV000485485	likely pathogenic	Microcephaly, normal intelligence and immunodeficiency	2015-12-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409031	SCV000553078	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser706*) 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 (rs730881857, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with prostate cancer and bladder cancer (PMID: 22864661). ClinVar contains an entry for this variant (Variation ID: 182728). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409031	SCV000917858	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2018-06-25	criteria provided, single submitter	clinical testing	Variant summary: NBN c.2117C>G (p.Ser706X) results in a premature termination codon, predicted to cause a truncation of the encoded protein in a highly conserved region of NBN near the MRE11 binding site due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 247890 control chromosomes (gnomAD and controls). The variant, c.2117C>G, has been reported in the literature in individuals affected with Hereditary Breast cancer, along with one family, Zuhkle_2012, in whom the variant was reported to partially co-segregate with prostate cancer. Individuals who are heterozygous for NBN mutations are clinically asymptomatic, but may display an elevated risk for certain cancers including, but not limited to, ovarian and prostate cancer as well as various lymphoid malignancies. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000409031	SCV002045313	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160795	SCV002536635	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-02-19	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003407597	SCV004107886	pathogenic	NBN-related disorder	2023-09-05	criteria provided, single submitter	clinical testing	The NBN c.2117C>G variant is predicted to result in premature protein termination (p.Ser706*). This patient is heterozygous in the NBN gene for a sequence variant defined as c.2117C>G, which is predicted to result in premature protein termination (p.Ser706*). This variant has been reported in a family with prostate cancer; however, the variant did not segregate with disease (Zuhlke et al. 2012. PubMed ID: 22864661). This variant has also been reported in individuals with melanoma and breast cancer (Aoude et al. 2020. PubMed ID: 33077847; Huang et al. 2018. PubMed ID: 29625052; Susswein et al. 2016. PubMed ID: 26681312). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-90955548-G-C). Nonsense variants in NBN are expected to be pathogenic for autosomal recessive disease, and this variant has been classified as pathogenic or likely pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182728/). This variant is interpreted as pathogenic.
Baylor Genetics	RCV003467263	SCV004199533	pathogenic	Aplastic anemia	2024-02-28	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535781	SCV001749939	not provided	Microcephaly, normal intelligence and immunodeficiency; Malignant tumor of breast		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 08-28-2017 by Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.