Submissions for variant NM_000059.4(BRCA2):c.1296_1297del (p.Asn433fs)

dbSNP: rs80359276

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031317	SCV000300417	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.
Invitae	RCV000043775	SCV000071788	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn433Glnfs*18) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a history of Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25682074, 25980754, 28008555). This variant is also known as 1524delGA. ClinVar contains an entry for this variant (Variation ID: 37736). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162900	SCV000213387	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-05	criteria provided, single submitter	clinical testing	The c.1296_1297delGA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 1296 to 1297, causing a translational frameshift with a predicted alternate stop codon (p.N433Qfs*18). This mutation was identified in a female diagnosed with triple negative breast cancer (Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80), and in a male diagnosed with breast cancer (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586). This alteration was identified in a cohort German patients considered to be at increased risk for HBOC syndrome (Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). In a large, clinic-based BRCA1/2 testing cohort in Norway, this variant was detected in one family (Heramb C et al. Hered Cancer Clin Pract. 2018 Jan;16:3). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000255901	SCV000296615	pathogenic	not provided	2023-07-17	criteria provided, single submitter	clinical testing	The BRCA2 c.1296_1297del (p.Asn433Glnfs*18) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 32393398 (2020), 32438681 (2020), 25682074 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
GeneDx	RCV000255901	SCV000321451	pathogenic	not provided	2023-05-09	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 significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with breast and/or ovarian cancer (Wong-Brown et al., 2015; Pritzlaff et al., 2016; Lang et al., 2017; Meisel et al., 2017; Arai et al., 2018; Carter et al., 2018); Also known as 1524_1525delGA; This variant is associated with the following publications: (PMID: 28008555, 28324225, 32438681, 25682074, 25980754, 29339979, 31825140, 32318955, 29176636, 30787465, 28294317, 30322717, 30702160, 32393398)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031317	SCV000326533	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031317	SCV000487833	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-21	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031317	SCV000605626	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031317	SCV000744406	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043775	SCV000916994	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1296_1297delGA (p.Asn433GlnfsX18) 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. The variant was absent in 120444 control chromosomes (ExAC). The variant, c.1296_1297delGA, has been reported in the literature in individuals affected with either sporadic or Hereditary Breast and Ovarian Cancer (Wong-Brown 2015, Pritzlaff 2017, Meisel 2017, Lang 2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; 8 laboratories classified the variant as pathogenic, and 1 as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000255901	SCV001247637	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2, PS4:Moderate
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031317	SCV001428739	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-07-12	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000255901	SCV001446782	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000255901	SCV002010738	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473158	SCV004211888	pathogenic	Familial cancer of breast	2023-10-09	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031317	SCV000053922	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-10-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031317	SCV000145847	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031317	SCV000733226	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357962	SCV001553576	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asn433GlnfsX18 variant was identified in 2 of 5484 proband chromosomes (frequency: 0.00036) from individuals or families with male breast cancer (Pritzlaff_2016_28008555), triple negative breast cancer (Wong-Brown_2015_25682074), and Lynch syndrome (Yurgelun_2017_28135145). The variant was also identified in dbSNP (ID: rs80359276) as “With Pathogenic allele”, ClinVar (as pathogenic reviewed by expert panel), Clinvitae (5x as [pathogenic), LOVD 3.0 (7x), UMD-LSDB (2x as causal), BIC Database (3x as pathogenic), and ARUP Laboratories (as definitely pathogenic) databases. The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Asn433GlnfsX18 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 433 and leads to a premature stop codon at position 450. 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 mechanism of disease 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.
BRCAlab, Lund University	RCV000031317	SCV004244192	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing