ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.631G>A (p.Val211Ile) (rs80358871)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213157 SCV000275759 pathogenic Hereditary cancer-predisposing syndrome 2017-11-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Breast Cancer Information Core (BIC) (BRCA2) RCV000113917 SCV000147341 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000213157 SCV000683772 pathogenic Hereditary cancer-predisposing syndrome 2017-02-27 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113917 SCV000327389 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000113917 SCV000677666 pathogenic Breast-ovarian cancer, familial 2 2016-12-05 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000496306 SCV000591699 pathogenic Hereditary breast and ovarian cancer syndrome 2015-10-22 criteria provided, single submitter clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735584 SCV000863722 pathogenic Breast and/or ovarian cancer no assertion criteria provided clinical testing
GeneDx RCV000214066 SCV000279589 pathogenic not provided 2018-01-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.631G>A at the cDNA level. Using alternate nomenclature, this variant would be defined as c.859G>A. Located in the last nucleotide of exon 7, it disrupts a natural splice donor site and causes abnormal splicing. Although the nucleotide substitution results in the change of a Valine to an Isoleucine at codon 211 and is called Val211Ile (V211I) in the literature, we are only using the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing, rather than a missense variant. This variant has been published as co-occurring with BRCA2 c.7008-2A>T in several probands and discussion of the combination of these variants is found in the subsequent interpretation. BRCA2 c.631G>A demonstrated skipping of exon 7 in both RT-PCR analyses of RNA and in a minigene assay (Pensabene 2009, Colombo 2009, Colombo 2013, Gaildrat 2012). BRCA2 c.631G>A was not observed in large population cohorts (Lek 2016). The nucleotide which is altered, a guanine (G) at base 631, is conserved across species. Based on currently available evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000496306 SCV000694962 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-15 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.631G>A (p.Val211Ile) variant causes a missense change involving a conserved position, however, the variant is located at the last 3' position of exon 7, known to affect splicing, with 5/5 splice prediction tools predicting a significant impact on splicing, which is supported by multiple functional studies. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications. Predominantly, the variant of interest has been reported to co-occur with another pathogenic BRCA2 variant, c.7008-2A>T. However, functional studies implicate that both variants do have a deleterious effect on splicing. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Mendelics RCV000496306 SCV000838740 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496306 SCV000587558 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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