ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1777C>G (p.Pro593Ala) (rs146989944)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656929 SCV000149694 uncertain significance not provided 2021-07-15 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of breast and/or ovarian cancer (Haiman 2013, Tung 2015); This variant is associated with the following publications: (PMID: 27535533, 25186627, 23555315)
Ambry Genetics RCV000115785 SCV000186185 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-09 criteria provided, single submitter clinical testing ​The p.P593A variant (also known as c.1777C>G), located in coding exon 11 of the NBN gene, results from an C to G substitution at nucleotide position 1777. The proline at codon 593 is replaced by alanine, an amino acid with highly similar properties. In our clinical cohort, this alteration <span style="background-color:initial">is frequently seen in conjunction with NBN p.F263S. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.<span style="background-color:initial"> Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000988083 SCV000254769 likely benign Microcephaly, normal intelligence and immunodeficiency 2020-12-06 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212750 SCV000595914 uncertain significance not specified 2016-04-27 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656929 SCV000806419 uncertain significance not provided 2017-07-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115785 SCV000902825 likely benign Hereditary cancer-predisposing syndrome 2016-06-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656929 SCV001134498 uncertain significance not provided 2019-07-16 criteria provided, single submitter clinical testing
Mendelics RCV000988083 SCV001137660 likely benign Microcephaly, normal intelligence and immunodeficiency 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212750 SCV001360495 likely benign not specified 2019-01-18 criteria provided, single submitter clinical testing Variant summary: NBN c.1777C>G (p.Pro593Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 276572 control chromosomes, predominantly at a frequency of 0.0022 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 17.6 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 origin. c.1777C>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Haiman_2013, Tung_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.2808_2811delACAA, p.Ala938fsX21), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, 4 classify as VUS while 1 classified as likley benign. Based on the evidence outlined above, the variant was classified as likely benign.

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