ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.628G>T (p.Val210Phe) (rs61754796)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000114880 SCV000149710 uncertain significance not provided 2021-05-17 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function Observed in individuals with a personal or family history of breast, ovarian, and other cancers (Varon 2001, Mosor 2006, Steffen 2006, Meyer 2007, Mateju 2012, Damiola 2014, Ramus 2015, Bueno 2016, Hauke 2018) This variant is associated with the following publications: (PMID: 19804756, 31278556, 11325820, 16810201, 16770759, 17496786, 22491912, 24894818, 26315354, 26928227, 29522266, 29844865, 29641532, 18606567, 26564480, 12353271, 29371908, 28873162, 26787654, 19452044, 24396275, 20805886, 24728327, 32668560)
Ambry Genetics RCV000115801 SCV000185891 likely benign Hereditary cancer-predisposing syndrome 2018-10-09 criteria provided, single submitter clinical testing No disease association in small case-control study;Other data supporting benign classification
Invitae RCV000168062 SCV000218716 likely benign Microcephaly, normal intelligence and immunodeficiency 2020-12-04 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000121622 SCV000248140 uncertain significance not specified 2015-01-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000114880 SCV000601697 likely benign not provided 2020-09-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515300 SCV000611491 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 RCV000121622 SCV000697975 likely benign not specified 2021-03-11 criteria provided, single submitter clinical testing Variant summary: NBN c.628G>T (p.Val210Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 267128 control chromosomes, predominantly at a frequency of 0.00077 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.628G>T has been reported in the literature in individuals affected with cancer including HBOC and ALL (e.g. Varon_2001, Mosor_2006, Steffen_2006, Mateju_2012, Damiola_2015, Ramus_2015, Bonache_2018, Dominguez-Valentin_2018, Hauke_2018, Dutil_2019) but it has also been reported in controls (e.g. Mateju_2012, Ramus_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic variant has been reported (BRCA2 c.9027delT, p.His3010IlefsX18; Internal testing), providing supporting evidence for a benign role. The variant was also reported in 16 women older than age 70 years who have never had cancer (FLOSSIES database) providing further evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and four ClinVar submitters (evaluation after 2014) cite it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000114880 SCV000806446 uncertain significance not provided 2017-11-15 criteria provided, single submitter clinical testing
Mendelics RCV000168062 SCV000838312 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115801 SCV000902597 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000114880 SCV001155448 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000121622 SCV001157433 uncertain significance not specified 2019-03-25 criteria provided, single submitter clinical testing The NBN c.628G>T; p.Val210Phe variant (rs61754796) is reported in the literature in individuals with melanoma, acute lymphoblastic leukemia, breast or ovarian cancer (Dominguez-Valentin 2018, Mateju 2012, Meyer 2007, Mosor 2006, Ramus 2015, Steffen 2006, Varon 2001), but is also reported in controls (Mateju 2012, Offer 2010, Ramus 2015). This variant is also found in the general population with an overall allele frequency of 0.04% (115/282316 alleles) in the Genome Aggregation Database. This variant is classified as uncertain by multiple laboratories in ClinVar (Variation ID: 127014). The valine at codon 210 is weakly conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Based on available information, the clinical significance of this variant is uncertain at this time. REFERENCES Dominguez-Valentin M et al. Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds. Hered Cancer Clin Pract. 2018 Jan 15;16:4. Mateju M et al. Germline mutations 657del5 and 643C>T (R215W) in NBN are not likely to be associated with increased risk of breast cancer in Czech women. Breast Cancer Res Treat. 2012 Jun;133(2):809-11. Meyer P et al. Molecular genetic analysis of NBS1 in German melanoma patients. Melanoma Res. 2007 Apr;17(2):109-16. Mosor M et al. Association of the heterozygous germline I171V mutation of the NBS1 gene with childhood acute lymphoblastic leukemia. Leukemia. 2006 Aug;20(8):1454-6. Offer SM et al. Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID. PLoS One. 2010 Aug 18;5(8):e12260. Ramus SJ et al. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J Natl Cancer Inst. 2015 Aug 27;107(11). Steffen J et al. Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland. Int J Cancer. 2006 Jul 15;119(2):472-5. Varon R et al. Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL). Cancer Res. 2001 May 1;61(9):3570-2.
Illumina Clinical Services Laboratory,Illumina RCV000168062 SCV001323246 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2017-08-29 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics RCV000168062 SCV001481562 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2019-08-27 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
ITMI RCV000121622 SCV000085820 not provided not specified 2013-09-19 no assertion provided reference population
Harris Lab, University of Minnesota RCV000114880 SCV000148775 not provided not provided no assertion provided not provided
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358247 SCV001553924 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The NBN p.Val210Phe variant was identified in 4 of 3654 proband chromosomes (frequency: 0.001) from individuals or families with melanoma, breast cancer, Non-Hodgkin lymphomas, ALL (Meyer_2007, Damiola_2014, Cerosaletti_2002, Varon_2001). The variant was also identified in the following databases: dbSNP (ID: rs61754796) as “With Uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Invitae, GSLUC; classified as likely benign by Ambry Genetics), Clinvitae (classified as uncertain significance by ClinVar, Invitae; classified as likely benign by ClinVar), and the Zhejiang Colon Cancer Database. The variant was not identified in Cosmic or LOVD 3.0, databases. The variant was identified in 116 of 276770 chromosomes at a frequency of 0.0004 in the following populations: African in 3 of 24004 chromosomes (freq. 0.000125), “other” in 3 of 6450 chromosomes (freq. 0.00046), Latino in 4 of 34354 chromosomes (freq. 0.000116), European in 97 of 126420 chromosomes (freq. 0.00076), Finnish in 5 of 25764 chromosomes (freq. 0.0002), and South Asian in 4 of 30782 chromosomes (freq. 0.00013), increasing the likelihood this could be a low frequency benign variant in certain populations (Genome Aggregation Consortium Feb 27, 2017). The p.Val210 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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. The variant is located with the Nibrin functional domain. 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000114880 SCV001808588 likely benign not provided no assertion criteria provided clinical testing

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