ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9235del (p.Val3079fs) (rs397507422)

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Total submissions: 14
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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) RCV000031804 SCV000301363 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000235872 SCV000293488 pathogenic not provided 2017-07-03 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.9235delG at the cDNA level and p.Val3079PhefsX4 (V3079FfsX4) at the protein level. The normal sequence, with the base that is deleted in braces, is TGTC[G]TTTC. The deletion causes a frameshift, which changes a Valine to a Phenylalanine at codon 3079, and creates a premature stop codon at position 4 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.9235delG, previously published as 9463delG using alternate nomenclature, has been observed in at least one Hispanic woman with ovarian cancer (Villarreal-Garza 2015). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031804 SCV000296569 pathogenic Breast-ovarian cancer, familial 2 2016-02-19 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031804 SCV000328080 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507914 SCV000602830 pathogenic not specified 2016-11-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509633 SCV000608023 pathogenic Hereditary cancer-predisposing syndrome 2019-04-12 criteria provided, single submitter clinical testing The c.9235delG pathogenic mutation, located in coding exon 23 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 9235, causing a translational frameshift with a predicted alternate stop codon (p.V3079Ffs*4). This mutation (designated as 9463delG) has been reported in a Hispanic female diagnosed with ovarian cancer (Villarreal-Garza C et al. Cancer. 2015 Feb 1;121(3):372-8). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000502775 SCV000635725 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val3079Phefs*4) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs397507422, ExAC 0.009%). This variant has been reported in the literature in an individual affected with ovarian cancer (PMID: 25236687). This variant is also known as 9463delG in the literature. ClinVar contains an entry for this variant (Variation ID: 38221). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000031804 SCV000677714 likely pathogenic Breast-ovarian cancer, familial 2 2015-06-11 criteria provided, single submitter clinical testing
Color Health, Inc RCV000509633 SCV000684039 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000502775 SCV000695220 pathogenic Hereditary breast and ovarian cancer syndrome 2019-07-29 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9235delG (p.Val3079PhefsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.2e-05 in 250876 control chromosomes, predominantly at a frequency of 0.0002 within the Latino subpopulation in the gnomAD database. c.9235delG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Villarreal-Garza_2015, Crawford_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (after 2014). All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Medicine Lab, University of California San Francisco RCV001007952 SCV001167666 pathogenic Polydactyly 2019-03-14 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031804 SCV000054412 pathogenic Breast-ovarian cancer, familial 2 2009-01-08 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000031804 SCV000592263 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The p.Val3079PhefsX4 deletion variant was not identified in the literature. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3079 and leads to a premature stop codon 4 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established disease mechanism in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735622 SCV000863760 pathogenic Breast and/or ovarian cancer 2015-02-13 no assertion criteria provided clinical testing

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