ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1317A>G (p.Ile439Met) (rs28538230)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001719859 SCV000149690 likely benign not provided 2020-09-21 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27443514, 25980754, 23555315, 26979391)
Ambry Genetics RCV000115781 SCV000186083 likely benign Hereditary cancer-predisposing syndrome 2018-04-20 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;Other data supporting benign classification
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000173760 SCV000224909 likely benign not specified 2014-07-16 criteria provided, single submitter clinical testing
Invitae RCV001082062 SCV000253385 benign Microcephaly, normal intelligence and immunodeficiency 2020-12-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000173760 SCV000697945 likely benign not specified 2020-10-26 criteria provided, single submitter clinical testing Variant summary: NBN c.1317A>G (p.Ile439Met) results in a conservative amino acid change in 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 0.00027 in 251276 control chromosomes, predominantly at a frequency of 0.0041 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. In addition, the variant was reported in 23/2559 African American women including 1 homozygote (i.e. with a frequency of 0.009), who were older than 70 years of age, and never had cancer (FLOSSIES database). These data strongly suggest that the variant is a benign polymorphism found primarily in populations of African origin. c.1317A>G has been reported in the literature in individuals affected with various tumor phenotypes (Yurgelun 2015, Ring 2016, Haiman 2013) including one homozygous germline occurrence in a colorectal cancer patient who was diagnosed over the age of 50 (Hampel 2018). These reports however, do not support the association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=6) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000173760 SCV000889546 benign not specified 2019-10-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115781 SCV000902680 benign Hereditary cancer-predisposing syndrome 2015-10-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001082062 SCV001327038 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.
Baylor Genetics RCV001292773 SCV001481420 uncertain significance Aplastic anemia 2019-01-13 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355697 SCV001550652 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The NBN p.Ile439Met variant was identified in 2 of 3282 proband chromosomes (frequency: 0.0006) from individuals or families with Lynch syndrome or endometrial carcinoma (Yurgelun 2015, Ring 2016). The variant was also identified in dbSNP (ID: rs28538230) as "With Likely benign allele", ClinVar (classified as likely benign by GeneDx, Ambry Genetics, Invitae, and three other clinical laboratories), and the Zhejiang University Databse (1x). The variant was not identified in Cosmic or LOVD 3.0 databases. The variant was identified in control databases in 96 of 277020 chromosomes at a frequency of 0.0004, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 95 of 24024 chromosomes (freq: 0.004), Latino in 1 of 34398 chromosomes (freq: 0.00003), while the variant was not observed in the Other, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ile439 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 but 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; however, 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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