Submissions for variant NM_000059.3(BRCA2):c.9403del (p.Leu3135fs)

dbSNP: rs80359760

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077470	SCV000282473	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000045813	SCV000073826	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52831). This variant is also known as 9630delC and 9631delC. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15024741, 15146557, 18489799, 21203900, 22160602). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu3135Phefs*28) 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).
Ambry Genetics	RCV000164828	SCV000215511	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	clinical testing	The c.9403delC pathogenic mutation, located in coding exon 24 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 9403, causing a translational frameshift with a predicted alternate stop codon (p.L3135Ffs*28). This alteration has been detected in multiple families with hereditary breast and/or ovarian cancer (Santarosa M et al. Int. J. Cancer. 1999 Sep;83:5-9; Grzybowska E et al. Hum. Mutat. 2000 Dec;16:482-90; Foretova L et al. Hum. Mutat. 2004 Apr;23:397-8; Górski B et al. Int J Cancer, 2004 Jul;110:683-6; Schneegans SM et al. Fam. Cancer. 2012 Jun;11:181-8; Wojcik P et al. Hered. Cancer Clin. Pract. 2016 Feb;14:5; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3). Of note, this alteration is also designated 9631delC, 9630delC, and 9402delC 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000077470	SCV000296640	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-04	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077470	SCV000328126	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077470	SCV000488275	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000414565	SCV000490441	pathogenic	not provided	2023-11-08	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9631delC; This variant is associated with the following publications: (PMID: 15146557, 21203900, 15024741, 22160602, 18489799, 26843898, 30787465, 30322717, 32341426, 33724863, 29922827, 29339979, 28888541, 31723001, 29446198, 31173646, 29534594, 33471991, 27376475)
Department of Medical Genetics, Oslo University Hospital	RCV000077470	SCV000605681	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045813	SCV000695237	pathogenic	Hereditary breast ovarian cancer syndrome	2017-01-04	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.9403delC (p.Leu3135Phefs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g.c.9331G>T/p.Glu3111X, c.9403delC/p.Leu3135fs). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in numerous HBOC patients and is absent in 121310 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077470	SCV000744564	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164828	SCV000903965	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 25 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 not been identified 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000414565	SCV001447445	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000077470	SCV001949998	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-07-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164828	SCV002532029	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-17	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000077470	SCV002579127	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-04-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496697	SCV002813962	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	2022-04-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473433	SCV004210513	pathogenic	Familial cancer of breast	2022-08-18	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077470	SCV000109268	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-07-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077470	SCV000147631	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000045813	SCV000588004	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353964	SCV000592284	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Leu3135PhefsX28 variant has been reported in the literature in 5/1088 proband chromosomes of high-risk breast/ ovarian cancer patients. However, no controls were tested to establish the frequency of the variant in the general population (Foretova 2004, Machackova 2008). This variant has been reported in a male breast cancer patient (Machackova 2008). It is listed in the dbSNP database (ID#: rs80359760) as coming from a clinical source. It has also been reported in the UMD (x2 as causal), BIC (x12 as clinically significant) and CNPHI (ACMG 2) databases. This variant is predicted to cause a frameshift, which alters the reading frame beginning at codon 3135 and leads to a premature stop codon, 28 codons downstream. This alteration is predicted to lead to a truncated or absent protein and loss of function. Loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast cancer patients. In summary, based on the above information, this variant is classified as Pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077470	SCV000733338	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077470	SCV004243872	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing