Submissions for variant NM_000059.4(BRCA2):c.1029del (p.Lys343fs)

dbSNP: rs80359260

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031305	SCV000300382	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.
Ambry Genetics	RCV000165362	SCV000216088	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	The c.1029delA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1029, causing a translational frameshift with a predicted alternate stop codon (p.K343Nfs*6). This mutation has been described in multiple breast and/or ovarian cancer patients (Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Meyer P et al. PLoS ONE. 2012;7:e38361; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026). In one case control study, this alteration was detected in 2/2222 individuals with invasive epithelial ovarian cancer and 0/1528 matched controls (Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9). 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.
GeneDx	RCV000218354	SCV000279590	pathogenic	not provided	2024-04-06	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; Also known as 1257delA; This variant is associated with the following publications: (PMID: 24728189, 24504028, 22666503, 11179017, 26556299, 29625052, 26689913)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000031305	SCV000296578	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-14	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031305	SCV000326485	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000496804	SCV000588075	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496804	SCV000694502	pathogenic	Hereditary breast ovarian cancer syndrome	2016-04-18	criteria provided, single submitter	clinical testing	Variant summary: The variant of interest causes a frameshift mutation resulting in a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest was not observed in controls (1000 Gs, ExAC or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant with a classification of "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000218354	SCV001247636	pathogenic	not provided	2018-03-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000218354	SCV001446999	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496804	SCV001581181	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys343Asnfs*6) 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 personal and/or family history of breast and/or ovarian cancer (PMID: 11179017, 21990299, 22666503, 24728189, 26556299). This variant is also known as 1257delA. ClinVar contains an entry for this variant (Variation ID: 37724). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031305	SCV001950105	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-08-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460497	SCV004213617	pathogenic	Familial cancer of breast	2023-09-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000218354	SCV004564539	pathogenic	not provided	2023-10-13	criteria provided, single submitter	clinical testing	The BRCA2 c.1029del; p.Lys343AsnfsTer6 variant (rs80359260), also known as 1257delA, is reported in the literature in several individuals affected with breast and/or ovarian cancer (Cunningham 2014, Meyer 2012, Risch 2001, Schrader 2016, Song 2014). This variant is reported in ClinVar (Variation ID: 37724), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Cunningham JM et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014 Feb 7;4:4026. PMID: 24504028. Meyer P et al. BRCA2 mutations and triple-negative breast cancer. PLoS One. 2012;7(5):e38361. PMID: 22666503. Risch HA et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001 Mar;68(3):700-10. PMID: 11179017. Schrader KA et al. Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. JAMA Oncol. 2016 Jan;2(1):104-11. PMID: 26556299. Song H et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014 Sep 1;23(17):4703-9. PMID: 24728189.
All of Us Research Program, National Institutes of Health	RCV000031305	SCV004836101	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-28	criteria provided, single submitter	clinical testing	This variant has been reported in multiple individuals with hereditary breast and ovarian cancer syndrome (PMID: 11179017, 22666503, 24728189, 24504028, 26556299, 29446198). This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This variant is present in 1/247832 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Sharing Clinical Reports Project (SCRP)	RCV000031305	SCV000053910	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-09-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031305	SCV000145808	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1999-04-12	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496804	SCV000587578	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research