ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.643C>T (p.Arg215Trp) (rs34767364)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000007363 SCV000166524 benign Microcephaly, normal intelligence and immunodeficiency 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115802 SCV000184001 likely benign Hereditary cancer-predisposing syndrome 2019-04-28 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Intact protein function observed in appropriate functional assay(s);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene;Subpopulation frequency in support of benign classification
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000487932 SCV000231654 uncertain significance not provided 2018-06-07 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487932 SCV000575564 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000121621 SCV000595910 likely benign not specified 2021-04-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000487932 SCV000601698 likely benign not provided 2020-01-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283459 SCV000604434 likely benign none provided 2020-06-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115802 SCV000685805 benign Hereditary cancer-predisposing syndrome 2014-12-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121621 SCV000697976 benign not specified 2019-11-01 criteria provided, single submitter clinical testing Variant summary: NBN c.643C>T (p.Arg215Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 269024 control chromosomes, predominantly at a frequency of 0.0042 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 34 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, the frequency in general population is in sub-polymorphic range and these data alone cannot rule out the possibility that it can still have a role as a risk variant in disease, although it has not been reported to have a considerably significant association with other forms of cancer (Taylor_2003, Hebbring_2006, Bogdanovaas_2008, Dzikiewicz-Krawczyk_2012, and Ramus_2014). This is consistent with studies reporting 95% CI around the OR to include 1.0, thereby providing little to no confidence on the strength of the assertions. Specifically, this variant was not significantly associated with increased risk for breast cancer (Bogdanova_2008) (adjusted OR = 1.9, 95%CI 0.84.6, p = 0.18) or prostate cancer (Hebbring_Cancer Epidemiol Biomarkers_2006) (OR = 1.24, 95CI 0.31-4.99, p = 0.77). Functional studies in compound heterozygotes with the 675del5 mutation have shown this variant to affect DNA repair and protein stability, however it is difficult from those studies to make conclusions about the effect of NBN Arg215Trp alone (Seemanova_2006, Bogdanova_2008, di Masi_2008, Mendez_2012). In addition, the variant did not increase chromosome breakage in cells (Seemanova_2006). It was found in a triple negative breast cancer cell line with alternate molecular basis for disease attributed to BRCA1, p.R715X mutation. Although the tumor specimen showed LOH for this NBN variant, the tumor histological characteristics and sensitivity of the cell line to PARP inhibitors can be attributed to the BRCA1 variant. Therefore, the overall implication of these functional data in causation of the NBS or cancer phenotype needs to be further clarified or is unknown (Schroder-Heurich_2014). Meanwhile, functional assays from heterozygous carriers of this variant have also shown the evidences of functional impairment (such as reduced expression of full-length nibrin, impairment in binding with gamma-H2AX and reduction in DNA-DSB rejoining) [Seemanova_2006, di Masi_2006, Dzikiewicz-Krawczyk_2012, and Schroder-Heurich_2014]. From a cell line that also carried BRCA1 p.R1751X, Schroder-Heurich_2014, reports that the (i) cells were highly radiosensitive, susceptible to apoptosis and were deficient in the formation of NBN foci, (ii) NBN was observed only at 30-40% of wildtype levels in the cells; and (iii) there was also evidence for some impairment in the formation of H2AX, MDC1, and 53BP1 foci after irradiation; and these foci appeared smaller and irregular compared with repair foci in wild-type cells, although ATM signaling was largely unaffected. The authors report that these functional consequences related to NBN are not explained by the BRCA1 mutation. This variant has been found in two severely NBS-affected siblings who were compound heterozygous for this variant and 657del5 (Seemanova_2006), although without increased chromosome breakage. Co-occurrences with other pathogenic variants have been reported (TP53 c.783-1G>A; BRCA2 c.8537_8538del, p.Glu2846Glyfs*22) (Yurgelun_2017, Tung_2016), providing supporting evidence for a benign role. 13 ClinVar submitters (evaluation after 2014) classified the variant as benign (1x), likely benign (4x), VUS (7x) and Pathogenic (1x). Based on the evidence outlined above, the variant was classified as benign.
Counsyl RCV000007363 SCV000800508 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2017-03-24 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000487932 SCV000806447 uncertain significance not provided 2016-08-23 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115802 SCV000822089 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000007363 SCV000838311 likely benign Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000007363 SCV001737335 likely benign Microcephaly, normal intelligence and immunodeficiency 2021-06-10 criteria provided, single submitter clinical testing
OMIM RCV000007363 SCV000027562 pathogenic Microcephaly, normal intelligence and immunodeficiency 2006-03-01 no assertion criteria provided literature only
ITMI RCV000121621 SCV000085819 not provided not specified 2013-09-19 no assertion provided reference population
GeneReviews RCV000007363 SCV000494626 pathogenic Microcephaly, normal intelligence and immunodeficiency 2017-02-02 no assertion criteria provided literature only
True Health Diagnostics RCV000115802 SCV000788081 likely benign Hereditary cancer-predisposing syndrome 2017-09-05 no assertion criteria provided clinical testing
Natera, Inc. RCV000007363 SCV001457051 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-01-10 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000007363 SCV001549892 likely benign Microcephaly, normal intelligence and immunodeficiency no assertion criteria provided clinical testing The NBN p.Arg215Trp variant was identified in 53 of 18583 proband chromosomes (frequency: 0.003) from Australian, North American, French Canadian, Macedonian, German, Belarusian, and Polish individuals or families with breast, ovarian or other cancers and was present in 19 of 15624 control chromosomes (frequency: 0.001) from healthy individuals (Damiola 2014, Desjardins 2009, Kostovska 2015, Bogdanova 2007, Steffen 2004, Ramus 2015, Kurian 2014). The variant was also identified in dbSNP (ID: rs34767364) as “With other allele”, ClinVar (classified with conflicting interpretations of pathogenicity including benign by Invitae, Color Genomics; likely benign by Ambry Genetics, ARUP Laboratories; uncertain significance by EGL Genetic Diagnostics, Genetic Services Laboratory-University of Chicago, Quest Diagnostics Nichols Institute San Juan Capistrano, Laboratory Corporation of America and Praxis fuer Humangenetik Tuebingen; pathogenic by GeneReviews and OMIM; and classification not provided by ITMI), Clinvitae (5x), LOVD 3.0 (1x), Zhejiang University Database (24x , co-occurring with pathogenic NBN variant c.657_661del/p.Lys219AsnfsX16), and was not identified in Cosmic. The variant was identified in control databases in 671 of 276666 chromosomes (3 homozygous) at a frequency of 0.002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 14 of 24000 chromosomes (freq: 0.0006), Other in 16 of 6452 chromosomes (freq: 0.002), Latino in 55 of 34344 chromosomes (freq: 0.002), European Non-Finnish in 502 (3 homozygous) of 126366 chromosomes (freq: 0.004), Ashkenazi Jewish in 3 of 10136 chromosomes (freq: 0.0003), Finnish in 79 of 25738 chromosomes (freq: 0.003), and South Asian in 2 of 30780 chromosomes (freq: 0.00007); it was not in the East Asian population. There is conflicting evidence in the literature as studies utilizing breast cancer cell lines from a heterozygous breast cancer patient carrying the variant and a truncating BRCA1 variant showed a 70% reduction of NBN protein expression, which was not seen in a BRCA1 cell line with wildtype NBN (Bogdanova 2007, Schroder-Heurich 2014). Seemanova et al (2005) also describe a dosage effect in twin boys affected with Nijmegen breakage syndrome, who are compound heterozygotes (with the founder mutation NBN 657del5), whereby the variant produced full length nibrin, but addition of the nonpolar Trp may still be associated with protein instability. In a large meta-analysis encompassing 60 independent publications, the variant was related to susceptibility to all cancers, but no significant risk was observed for breast cancer (Gao 2013). The p.Arg215 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Trp 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, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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