Submissions for variant NM_000059.4(BRCA2):c.6724_6725del (p.Asp2242fs)

dbSNP: rs397507375

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031644	SCV000301100	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031644	SCV000327506	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509953	SCV000608045	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-13	criteria provided, single submitter	clinical testing	The c.6724_6725delGA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 6724 to 6725, causing a translational frameshift with a predicted alternate stop codon (p.D2242Ffs*2). This mutation has been reported in multiple Korean patients and families with breast and/or ovarian cancer, including individuals diagnosed with triple negative breast cancer (Kwong A et al. J Med Genet. 2016 Jan;53:15-23; Rebbeck TR et al. Hum. Mutat. 2018 May;39:593-620; Ryu JM et al. Breast Cancer Res Treat. 2019 Jan;173:385-395). 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	RCV000758932	SCV000887886	pathogenic	not provided	2018-06-29	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. Additionally, this variant has been reported in an individual with breast cancer in the published literature (PMID: 19656164 (2009)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000509953	SCV000903720	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-16	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 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 reported in individuals affected with breast and/or ovarian cancer and in high-risk breast and ovarian cancer families (PMID: 19656164, 22217648, 22382806, 22798144, 25863477, 26187060, 27836010, doi:10.21203/rs.3.rs-734551/v1), and has also been identified in 6 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 1/251336 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496792	SCV001583922	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp2242Phefs*2) 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 (rs397507375, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 19656164, 22217648, 22382806, 22798144, 25863477). This variant is also known as 6952delGA. ClinVar contains an entry for this variant (Variation ID: 38062). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000758932	SCV001779196	pathogenic	not provided	2023-06-28	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; Reported in association with hereditary breast and ovarian cancer, and identified as a recurrent pathogenic variant in individuals of Korean ancestry (Han et al., 2011; Kwong et al., 2016; Ryu et al., 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 6952_6953del; This variant is associated with the following publications: (PMID: 25863477, 29922827, 19656164, 27836010, 26187060, 29446198, 22798144, 29346284, 30350268, 21497495, 30720243, 31447099, 34645131)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496792	SCV003933902	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6724_6725delGA (p.Asp2242PhefsX2) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251336 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6724_6725delGA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Kang_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 25863477). Seven ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003460525	SCV004216029	pathogenic	Familial cancer of breast	2023-07-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000758932	SCV004565026	pathogenic	not provided	2023-04-10	criteria provided, single submitter	clinical testing	The BRCA2 c.6724_6725del; p.Asp2242PhefsTer2 variant (rs397507375), also known as 6952delGA, is reported in individuals with breast cancer (Bang 2022, Ryu 2019, Seong 2009). This variant is also reported in ClinVar (Variation ID: 38062). It is only found on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, 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: Bang YJ et al. Clinicopathological Characterization of Double Heterozygosity for BRCA1 and BRCA2 Variants in Korean Breast Cancer Patients. Cancer Res Treat. 2022 Jul;54(3):827-833. PMID: 34645131. Ryu JM et al. Prevalence and oncologic outcomes of BRCA 1/2 mutations in unselected triple-negative breast cancer patients in Korea. Breast Cancer Res Treat. 2019 Jan;173(2):385-395. PMID: 30350268. Seong MW et al. Comprehensive mutational analysis of BRCA1/BRCA2 for Korean breast cancer patients: evidence of a founder mutation. Clin Genet. 2009 Aug;76(2):152-60. PMID: 19656164.
All of Us Research Program, National Institutes of Health	RCV000031644	SCV004844305	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-09	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 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 reported in individuals affected with breast and/or ovarian cancer and in high-risk breast and ovarian cancer families (PMID: 19656164, 22217648, 22382806, 22798144, 25863477, 26187060, 27836010, doi:10.21203/rs.3.rs-734551/v1), and has also been identified in 6 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 1/251336 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000496792	SCV005045790	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-05	criteria provided, single submitter	clinical testing	The c.6724_6725del (p.Asp2242Phefs*2) variant in the BRCA2 gene is located on the exon 11 and is predicted to shift the reading frame that introduces a premature translation termination codon (p.Asp2242Phefs*2), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast and/or ovarian cancer (PMID: 34657357, 22217648, 19656164, 26187060). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 38062) and reviewed by the expert panel. The variant is rare in general population according to gnomAD (1/251336). Therefore, the c.6724_6725del (p.Asp2242Phefs*2) variant in the BRCA2 gene has been classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031644	SCV000054251	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-02-14	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496792	SCV000587866	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research