Submissions for variant NM_002485.5(NBN):c.505C>T (p.Arg169Cys)

gnomAD frequency: 0.00011  dbSNP: rs182756889

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587269	SCV000149705	uncertain significance	not provided	2024-08-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, pancreatic, and other cancers, but also in healthy control groups and in an individual with breast cancer and a co-occurring truncating BRCA1 variant (PMID: 25712764, 25503501, 25980754, 29522266, 30287823, 30982232, 33309985, 32068069, 32980694); This variant is associated with the following publications: (PMID: 25712764, 25980754, 25503501, 29522266, 33309985, 33800431, 36632296, 24894818, 25186627, 31666926, 32068069, 32980694, 32566746, 30287823, 30982232, 36427680, 36346689)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123218	SCV000166523	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 169 of the NBN protein (p.Arg169Cys). This variant is present in population databases (rs182756889, gnomAD 0.06%). This missense change has been observed in individual(s) with breast cancer (PMID: 25503501, 25712764, 25980754). ClinVar contains an entry for this variant (Variation ID: 127873). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV000115796	SCV000186755	likely benign	Hereditary cancer-predisposing syndrome	2022-09-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000123218	SCV000475300	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2018-01-12	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001549273	SCV000697971	uncertain significance	not specified	2024-10-07	criteria provided, single submitter	clinical testing	Variant summary: NBN c.505C>T (p.Arg169Cys) results in a non-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 0.00023 in 298708 control chromosomes (gnomAD and Momozawa_2018). The observed variant frequency in East Asia is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.00049 vs 0.00013), strongly suggesting that the variant is benign. c.505C>T has been reported in the literature in individuals affected with various types of cancers including but not limiting to breast and/or ovarian cancer, colorectal cancer, nasopharyngeal cancer and gall bladder cancer (example: Fujita_2020, Kwong_2020, Momozawa_2018, Terashima_2019, Wang_2018). 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: 36346689, 33309985, 33800431, 25712764, 32068069, 25503501, 30287823, 31666926, 25186627, 30982232, 25980754). ClinVar contains an entry for this variant (Variation ID: 127873). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics, part of Exact Sciences	RCV003389690	SCV000806443	uncertain significance	NBN-related disorder	2023-05-17	criteria provided, single submitter	clinical testing	The NBN c.505C>T variant is predicted to result in the amino acid substitution p.Arg169Cys. This variant has been observed within individuals with early-onset breast cancer and suspected Lynch syndrome (Maxwell et al. 2015. PubMed ID: 25503501, Supplementary Table 1; Yurgelun et al. 2015. PubMed ID: 25980754, Supplementary Table 2). However, this variant has also been reported in control cohorts (Supplemental Data 2, Momozawa et al. 2018. PubMed ID: 30287823). This variant is reported in 0.065% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-90990527-G-A) and in ClinVar has conflicting interpretations ranging from 'likely benign' to a ‘variant of uncertain significance’ (https://www.ncbi.nlm.nih.gov/clinvar/variation/127873/). While we suspect that this variant is likely benign, at this time we interpret its clinical significance as uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587269	SCV000889550	uncertain significance	not provided	2023-05-07	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00065 (13/19954 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 25503501 (2015), 25712764 (2015)), familial breast and/or ovarian cancer (PMID: 25980754 (2019), 32068069 (2020)), suspected Lynch syndrome (PMID: 25980754 (2015)), biliary tract carcinoma (PMID: 31666926 (2019)), pancreatic cancer (PMID: 32980694 (2020)), and colorectal cancer (PMID: 33309985 (2020)). This variant has also been reported in unaffected individuals (PMID: 32980694 (2020), 33309985 (2020)). 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.
Fulgent Genetics, Fulgent Genetics	RCV000764786	SCV000895930	uncertain significance	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2018-10-31	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030567	SCV001193657	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Genome-Nilou Lab	RCV000123218	SCV002045965	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115796	SCV002536689	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115796	SCV005045360	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000123218	SCV001461772	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-09-16	no assertion criteria provided	clinical testing