ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9234C>T (p.Val3078=) (rs587782428)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000495698 SCV000578815 likely benign Breast-ovarian cancer, familial 2 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02;
Ambry Genetics RCV000131482 SCV000186469 likely benign Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing In silico models in agreement (benign);RNA Studies
Invitae RCV001083240 SCV000259605 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131482 SCV000684038 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-22 criteria provided, single submitter clinical testing This variant causes a C>T nucleotide change in exon 24 of the BRCA2 gene. Splice site prediction tools suggest that this variant may not impact RNA splicing. An RNA study reported that the variant caused the partial skipping of exon 24 in RT-PCR analysis of carrier-derived lymphocyte RNA, but primary data were not provided for evaluation (PMID: 20215541). This variant has been reported in an individual affected with breast cancer, who also had a pathogenic BRCA1 variant (PMID: 20215541). This variant has been identified in 5/282222 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000608709 SCV000695219 likely benign not specified 2020-11-21 criteria provided, single submitter clinical testing
GeneDx RCV000608709 SCV000730936 benign not specified 2015-09-14 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.
Counsyl RCV000495698 SCV000785176 uncertain significance Breast-ovarian cancer, familial 2 2017-05-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590584 SCV000889177 likely benign not provided 2019-08-31 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355135 SCV001549924 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Val3078= variant was identified in 2 of 2180 proband chromosomes (frequency: 0.0009) from individuals or families with breast or ovarian cancer (Sanz 2010, Schenkel 2016). The variant was also identified in dbSNP (ID: rs587782428) as “With Uncertain significance allele”, ClinVar (8x as benign, likely benign and uncertain significance by ENIGMA, Color, Integrated Genetics, GeneDx, Counsyl, Quest, Ambry Genetic, Invitae) and LOVD 3.0 (2x as VUS and likely benign).The variant was not identified in UMD-LSDB. The variant was also identified by our laboratory in 1 individual with BRCA. The variant was identified in control databases in 3 of 276678 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 34360 chromosomes (freq: 0.00003), European Non-Finnish in 2 of 126488 chromosomes (freq: 0.000016), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The p.Val3078= 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) do not predict a difference in splicing. However, in a study by (Sanz 2010), bioinformatics programs predicted the disruption of an exonic splicing enhancer and the creation of exonic splicing silencers; in addition, mRNA analysis of the variant in this study showed partial exon 24 skipping, with a predicted partial truncation of protein product. In this same study the variant was identified in a patient with a co-occurring BRCA1 c.4165_4166delAG pathogenic variant providing conflicting evidence. 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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