ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.441C>T (p.Cys147=) (rs137857529)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198138 SCV000253391 benign not provided 2019-02-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000214383 SCV000274720 likely benign Hereditary cancer-predisposing syndrome 2015-03-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508575 SCV000601695 likely benign not specified 2017-02-22 criteria provided, single submitter clinical testing
Color RCV000214383 SCV000685784 likely benign Hereditary cancer-predisposing syndrome 2015-06-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000508575 SCV000697970 likely benign not specified 2019-03-08 criteria provided, single submitter clinical testing Variant summary: NBN c.441C>T results in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 277008 control chromosomes, predominantly at a frequency of 0.0018 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 14.4 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. To our knowledge, no occurrence of c.441C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant three times as likely benign and once as benign. Based on the evidence outlined above, the variant was classified as likely benign.

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