ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.1354A>C (p.Thr452Pro)

gnomAD frequency: 0.00067  dbSNP: rs141137543
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131458 SCV000186442 likely benign Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000735122 SCV000211450 likely benign not provided 2020-07-06 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function This variant is associated with the following publications: (PMID: 30564542, 27443514, 26976419, 25980754, 30309722)
Invitae RCV000199946 SCV000253386 likely benign Microcephaly, normal intelligence and immunodeficiency 2021-12-17 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000212747 SCV000595915 uncertain significance not specified 2017-02-07 criteria provided, single submitter clinical testing
Mendelics RCV000199946 SCV000838303 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing
Eurofins NTD LLC (GA) RCV000735122 SCV000863322 uncertain significance not provided 2018-09-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000212747 SCV000885816 uncertain significance not specified 2019-04-05 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131458 SCV000910678 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212747 SCV000917862 likely benign not specified 2019-06-03 criteria provided, single submitter clinical testing Variant summary: NBN c.1354A>C (p.Thr452Pro) results in a non-conservative amino acid change located in the outside of any known functional domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 251218 control chromosomes, predominantly at a frequency of 0.0026 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 20.8 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 African or African-American origin. Moreover, the variant was also identified in 22/2559 African American and 1/7325 of European American women who are cancer free at age over 70 in the FLOSSIES database. c.1354A>C has been reported in the literature in individuals affected with Breast cancer, Endometrial cancer and Lynch syndrome (Tung 2016, Ring 2016, Kolli_2018, and Yurgelun 2015). In two of these publications, co-occurrences with a pathogenic variant have been reported (MLH1 c.677G>A, p.Arg226Gln; PALB2 c.3027delT, p.Glu1010Argfs), providing supporting evidence for a benign role in the patient with Lynch Syndrome and breast cancer, respectively (Yurgelun 2015, Kolli_2018). Additionally, an internal sample also carries the variant of interest and MLH1 c.677G>A (pathogenic). A case control study found the variant to occur mainly in the African American cohort, both in breast cancer cases and controls, however sample sizes in each racial/ethnic group were relatively small to establish a clear relationship between the variant and breast cancer risk (Haiman 2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight 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 (3 likely benign, 5 VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000735122 SCV001134493 likely benign not provided 2019-12-17 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000199946 SCV002045920 likely benign Microcephaly, normal intelligence and immunodeficiency 2021-11-07 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV002225444 SCV002505291 likely benign Hereditary breast ovarian cancer syndrome 2022-04-19 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000131458 SCV002536593 likely benign Hereditary cancer-predisposing syndrome 2021-08-11 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000735122 SCV001549968 uncertain significance not provided no assertion criteria provided clinical testing The NBN p.Thr452Pro variant was identified in 2 of 1738 proband chromosomes (frequency: 0.001) from individuals or families with breast or endometrial cancer (Tung 2016, Ring 2016). The variant was also identified with one other NBN variant and a PALB2 variant, in one individual with primary male breast cancer and primary prostate cancer, though its significance was not conclusive (Kolli 2018). The variant was also identified in dbSNP (ID: rs141137543) as "With other allele", in ClinVar (classified as likely benign by GeneDx and Invitae; uncertain significance by Ambry Genetics, University of Chicago, Mendelics, EGL and ARUP Laboratories), LOVD 3.0 (classified as effect unknown by one submitter). The variant was identified in control databases in 72 of 276950 chromosomes at a frequency of 0.0003 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 61 of 24010 chromosomes (freq: 0.003), Other in 1 of 6456 chromosomes (freq: 0.0002), Latino in 9 of 34394 chromosomes (freq: 0.0003), European Non-Finnish in 1 of 126548 chromosomes (freq: 0.000008); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr452 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 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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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