ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.381T>C (p.Ala127=) (rs61754795)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000988088 SCV000153939 benign Microcephaly, normal intelligence and immunodeficiency 2020-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000178181 SCV000170645 benign not specified 2013-10-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000157764 SCV000212663 likely benign Hereditary cancer-predisposing syndrome 2014-07-01 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000178181 SCV000230195 benign not specified 2015-03-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000157764 SCV000537390 benign Hereditary cancer-predisposing syndrome 2015-04-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000178181 SCV000539868 likely benign not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple assertions in clinvar as benign for hereditary cancer predisposing syndrome and microcephaly with normal intelligence and immunodeficiency
Genetic Services Laboratory, University of Chicago RCV000178181 SCV000595911 likely benign not specified 2016-07-13 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000178181 SCV000806439 benign not specified 2017-02-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000119323 SCV000888340 benign not provided 2018-10-17 criteria provided, single submitter clinical testing
Mendelics RCV000988088 SCV001137668 likely benign Microcephaly, normal intelligence and immunodeficiency 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000119323 SCV001155449 likely benign not provided 2019-02-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282656 SCV001156821 benign none provided 2020-02-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000988088 SCV001324899 likely benign 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Harris Lab, University of Minnesota RCV000119323 SCV000154182 not provided not provided no assertion provided not provided
True Health Diagnostics RCV000157764 SCV000788080 likely benign Hereditary cancer-predisposing syndrome 2017-09-21 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000119323 SCV001550870 likely benign not provided no assertion criteria provided clinical testing The NBN p.Ala127Ala variant was identified in 1 of 194 proband chromosomes (frequency: 0.005) from French Canadian individuals or families non BRCA1/2 breast cancer and was not identified in 144 control chromosomes from healthy individuals (Desjardins 2009). The variant was also identified in dbSNP (ID: rs61754795) “With other allele”, ClinVar (classified benign by GeneDx, EGL Genetic Diagnostics (Eurofins Clinical Diagnsotics), Color Genomics Inc, Invitae; likely benign by Ambry Genetics and Lab for Molecular Medicine (Partners HealthCare Personalized Medicine); and classification not provided by Harris Lab (U of Minnesota)), Clinvitae (4x), and was not identified in Cosmic, LOVD 3.0, Zhejiang Colon Cancer Database. The variant was identified in control databases in 858 (4 homozygous) of 276910 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 26 of 24026 chromosomes (frequency: 0.001), Other in 16 of 6456 chromosomes (frequency: 0.002), Latino in 54 of 34414 chromosomes (frequency: 0.002), European Non-Finnish in 499 of 126588 chromosomes (frequency: 0.004), European Finnish in 20 of 25630 chromosomes (frequency: 0.0008), Ashkenazi Jewish in 4 of 10150 chromosomes (frequency: 0.0004), and South Asian in 239 (4 homozygotes) of 30782 chromosomes (frequency: 0.008). The p.Ala127= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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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