ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.425A>G (p.Asn142Ser) (rs769414)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589414 SCV000149703 likely benign not provided 2020-08-23 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23525077, 26315354, 24728327, 26787654, 24894818, 26979391, 26193622, 12376507, 12427538, 31278556)
Ambry Genetics RCV000115794 SCV000186535 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-13 criteria provided, single submitter clinical testing The p.N142S variant (also known as c.425A>G), located in coding exon 4 of the NBN gene, results from an A to G substitution at nucleotide position 425. The asparagine at codon 142 is replaced by serine, an amino acid with highly similar properties. This alteration was observed in an individual with breast cancer diagnosed prior to age 45 years (Young EL et al. J Med Genet. 2016 06;53:366-76) as well as in 2/3236 cases with invasive epithelial ovarian cancer and 1/3431 controls in another study (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107). However, this alteration has also been observed in 0/1313 early-onset breast cancer cases and in 1/1123 population controls in a different case-control study and was also identified in a cohort of 681 ancestrally diverse, healthy subjects (Damiola F et al. Breast Cancer Res. 2014 Jun;16:R58; Bodian DL et al. PLoS ONE. 2014 Apr;9:e94554). This amino acid position is not well 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.
Invitae RCV000168260 SCV000218931 likely benign Microcephaly, normal intelligence and immunodeficiency 2020-12-06 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000121617 SCV000248138 uncertain significance not specified 2015-06-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589414 SCV000601693 uncertain significance not provided 2019-11-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515292 SCV000611488 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2017-05-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121617 SCV000697969 likely benign not specified 2018-11-12 criteria provided, single submitter clinical testing Variant summary: NBN c.425A>G (p.Asn142Ser) results in a conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 284406 control chromosomes (gnomAD and publications). The observed variant frequency is approximately 1.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), suggesting that the variant might be benign. The variant, c.425A>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Ramus_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign x2, VUS x6). Our laboratory classified this variant as a "VUS-possibly normal" in October-2016, however, no new evidence supporting pathogenicity have been reported and at-least two other testing laboratories have classified this variant as likely benign since our original classification. Therefore, the overall evidence seems to be shifting from uncertain significance to likely benign consistent with a variant frequency in unaffected much higher than expected from disease prevalence. Based on the evidence outlined above, until more clinical and functional data become available, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000589414 SCV000806440 uncertain significance not provided 2017-06-02 criteria provided, single submitter clinical testing
Mendelics RCV000168260 SCV000838315 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115794 SCV000910599 likely benign Hereditary cancer-predisposing syndrome 2016-01-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000168260 SCV001324898 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-01-13 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.
Nilou-Genome Lab RCV000168260 SCV001653360 likely benign Microcephaly, normal intelligence and immunodeficiency 2021-05-18 criteria provided, single submitter clinical testing
ITMI RCV000121617 SCV000085815 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355243 SCV001550070 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The NBN p.Asn142Ser variant was identified in 4 of 9094 proband chromosomes (frequency: 0.0004) from individuals or families with myeloproliferative neoplasms, epithelial ovarian cancer, or breast cancer and in 4 of 8224 control chromosomes (frequency: 0.0005) from healthy individuals (Bodian 2014, Pratz 2016, Ramus 2015, Young 2016). The variant was also identified in dbSNP (ID: rs769414) as "With other allele", ClinVar (classified as likely benign by Invitae and GeneDx; and as uncertain significance by Ambry Genetics and four other clinical laboratories), Cosmic (1x in oesophagus), LOVD 3.0 (1x), and Zhejiang University database. The variant was identified in control databases in 47 of 277032 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 24 of 126600 chromosomes (freq: 0.0002), African in 1 of 24028 chromosomes (freq: 0.00004), Other in 7 of 6460 chromosomes (freq: 0.001), Latino in 12 of 34412 chromosomes (freq: 0.0004), Ashkenazi Jewish in 2 of 10148 chromosomes (freq: 0.0002), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the East Asian or Finnish populations. The p.Asn142 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.

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