ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9117G>A (p.Pro3039=) (rs28897756)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131039 SCV000185969 pathogenic Hereditary cancer-predisposing syndrome 2018-01-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Breast Cancer Information Core (BIC) (BRCA2) RCV000031798 SCV000147546 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000131039 SCV000537643 pathogenic Hereditary cancer-predisposing syndrome 2015-10-21 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031798 SCV000328057 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031798 SCV000488254 pathogenic Breast-ovarian cancer, familial 2 2016-02-03 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031798 SCV000744555 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000031798 SCV000605690 pathogenic Breast-ovarian cancer, familial 2 2015-11-02 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031798 SCV000733331 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000031798 SCV000575743 pathogenic Breast-ovarian cancer, familial 2 2015-09-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515207 SCV000611181 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3; Tracheoesophageal fistula 2017-05-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763330 SCV000894007 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000074560 SCV000108645 pathogenic not provided 2018-08-03 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.9117G>A at the DNA level. Although this variant is silent at the coding level, preserving a Proline at codon 3039, it disrupts a splice donor site and has been shown in functional assays to cause aberrant RNA processing, specifically skipping of exon 23 (Peelan 2000, Bonatti 2006, Colombo 2013). Previously reported as BRCA2 9345G>A (del exon 23), this variant has been observed in multiple breast/ovarian cancer families (Peelan 2000, Risch 2006, Novakovic 2012, Tea 2014, de Juan 2015, Gabald? Barrios 2017). BRCA2 c.9117G>A was not observed in large population cohorts (Lek 2016). Based on currently available evidence, we consider this variant to be pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000031798 SCV000743359 pathogenic Breast-ovarian cancer, familial 2 2014-10-10 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000031798 SCV000839919 pathogenic Breast-ovarian cancer, familial 2 2017-05-25 criteria provided, single submitter clinical testing The c.9117G>A (p.Pro3039Pro) variant in the BRCA2 gene has been detected in multiple patients and families with breast and/or ovarian cancer [PMID 10638982 reported as 3398delAAAAG, 27000661] and a cohort of patients with prostate cancer [PMID 23035815, reported as c.9117 G>A (p.Val2985fs)]. The nucleotide position 9117 is the last nucleotide of exon 23. Several in vitro assays showed that the change leads aberrant splicing and the skipping of exon 23 [PMID 22505045, 23451180]. This variant is thus predicted to result in a loss of function of the protein. This variant has not been reported in the ExAC database. This variant thus classified as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000045725 SCV000494420 pathogenic Hereditary breast and ovarian cancer syndrome 2015-08-10 criteria provided, single submitter clinical testing Variant Summary: The variant of interest is a conserved nucleotide that causes a synonymous change, however, the variant is located at the exon/intron junction at the 3'end of exon 23 and predicted to be disease-causing by Mutation Taster. 3/5 in silico programs via Alamut predict the elminiation of a splice site and the removal of an ESE binding motif. The effect of this variant on splicing has been evaluated by multiple functional studies (Acedo_2012, Bonatti_2006, Colombo_2013, and Houdayer_2012), which all consistently showed the skipping of exon 23. The variant of interest has reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories, BIC, UMD, kConFab, ARUP, HGMD, Ambry Genetics, GeneDx, and SCRP, cites the variant with a classification of "pathogenic." Therefore, taking all lines of evidence into consideration, the variant of interest is classified as pathogenic.
Invitae RCV000045725 SCV000073738 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change affects codon 3039 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. It also falls at the last nucleotide of exon 23 of the BRCA2 coding sequence. This variant is not present in population databases (rs28897756, ExAC no frequency). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 10638982, 17011978, 22923021, 17148771, 26026974), and prostate cancer (PMID: 23035815). This variant is also known as 9345G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 38215). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this sequence change causes aberrant splicing, leading to skipping of exon 23 of the BRCA2 mRNA. This leads to a frameshift at codon 2985 and a premature stop signal (Val2985Glyfs*3), and is expected to result in an absent or disrupted protein product (PMID: 22632462, 23451180, 22505045, 25382762, 23035815). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000045725 SCV000838896 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074560 SCV000296758 pathogenic not provided 2015-02-17 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045725 SCV000587988 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031798 SCV000054406 pathogenic Breast-ovarian cancer, familial 2 2013-08-31 no assertion criteria provided clinical testing

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