ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.365-7C>T

gnomAD frequency: 0.00004  dbSNP: rs745929983
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001085416 SCV000259615 likely benign Familial cancer of breast 2021-12-17 criteria provided, single submitter clinical testing
GeneDx RCV000439932 SCV000512236 likely benign not specified 2017-07-11 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000206530 SCV000600196 likely benign not provided 2021-02-11 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000581028 SCV000682785 likely benign Hereditary cancer-predisposing syndrome 2016-03-04 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000439932 SCV002067946 likely benign not specified 2021-09-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000439932 SCV002500621 uncertain significance not specified 2022-03-24 criteria provided, single submitter clinical testing Variant summary: BARD1 c.365-7C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 3.8e-05 in 238706 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.365-7C>T has been reported in the literature in individuals affected with Hereditary Breast Cancer without evidence for causality (example: De Brakeleer_2010) . This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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 and all classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4,Sema4 RCV000581028 SCV002529615 likely benign Hereditary cancer-predisposing syndrome 2022-02-04 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356627 SCV001551848 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BARD1 c.365-7C>T variant was identified in 1 of 392 proband chromosomes (frequency: 0.003) from individuals or families with breast cancer (De Brakeleer 2010). The variant was identified in dbSNP (rs745929983) as “with likely benign allele” and ClinVar (classified as likely benign by Invitae, Color, GeneDx and Quest Diagnostics). The variant was identified in control databases in 10 of 269,488 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6824 chromosomes (freq: 0.0001), Latino in 2 of 33,564 chromosomes (freq: 0.00006), European in 6 of 123,604 chromosomes (freq: 0.00005), and African in 1 of 23,536 chromosomes (freq: 0.00004), while it was not observed in the Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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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