Submissions for variant NM_000059.4(BRCA2):c.9235del (p.Val3079fs)

gnomAD frequency: 0.00003  dbSNP: rs397507422

Total submissions: 18

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, susceptibility to, 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	2023-11-28	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9463del; This variant is associated with the following publications: (PMID: 26564481, 29922827, 25236687, 26295337, 30720243, 30630528, 30787465, 34196900, 32191290, 28281021, 29446198, 31853058, 20104584, 36232851, 32064343, 37664050)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235872	SCV000296569	pathogenic	not provided	2021-08-20	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in an individual affected with ovarian cancer (PMID: 25236687 (2015)). The frequency of this variant in the general population, 0.0002 (7/34434 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031804	SCV000328080	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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	2022-05-26	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 alteration 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). Of note, this alteration is also known as 9463delG in published literature. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000502775	SCV000635725	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-04	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. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs397507422, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 25236687). This variant is also known as 9463delG. ClinVar contains an entry for this variant (Variation ID: 38221). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000031804	SCV000677714	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-06-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000509633	SCV000684039	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 24 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 8/250876 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000502775	SCV000695220	pathogenic	Hereditary breast ovarian cancer syndrome	2021-09-28	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 Syndrome (example, Villarreal-Garza 2015, Crawford 2017, Rebbeck 2018). These data indicate that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. 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
Fulgent Genetics, Fulgent Genetics	RCV002504847	SCV002811058	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2021-11-22	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000502775	SCV002819222	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-06-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532467	SCV004119290	pathogenic	BRCA2-related disorder	2022-11-17	criteria provided, single submitter	clinical testing	The BRCA2 c.9235delG variant is predicted to result in a frameshift and premature protein termination (p.Val3079Phefs*4). This variant, also known as 9463delG, has been reported in individuals with breast and/or ovarian cancer (Crawford et al. 2017. PubMed ID: 28281021. eTable 3; Rebbeck et al. 2018. PubMed ID: 29446198; Fernández-Lopez et al. 2019. PubMed ID: 30630528). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32954260-CG-C). In ClinVar, this variant is interpreted as pathogenic/likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/38221/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003473228	SCV004210435	pathogenic	Familial cancer of breast	2022-12-08	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031804	SCV000054412	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 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