Submissions for variant NM_000059.4(BRCA2):c.6757_6758del (p.Leu2253fs)

dbSNP: rs80359623

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113638	SCV000301104	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045041	SCV000073054	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu2253Phefs*7) 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 (rs80359623, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 11606101). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162933	SCV000213420	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	The c.6757_6758delCT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 6757 to 6758, causing a translational frameshift with a predicted alternate stop codon (p.L2253Ffs*7). This pathogenic mutation, also referred to as 6985delCT in published literature, has been reported in an individual with a diagnosis of breast and ovarian cancer at ages 51 and 68, respectively, and family history of a sister with breast cancer at an unspecified age (Schorge JO et al. Gynecol. Oncol. 2001 Nov;83:383-7). This alteration was also identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). This mutation occurs in a region of the BRCA2 gene known as the "ovarian cancer cluster region (OCCR)." Mutations in this region are associated with a significantly higher ratio of ovarian to breast cancer in female carriers than female carriers of mutations in other regions of the gene (p<0.0001) (Rebbeck TR et al. JAMA. 2015 Apr;313:1347-61). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113638	SCV000327515	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000522313	SCV000617470	pathogenic	not provided	2023-02-17	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 6985delCT; This variant is associated with the following publications: (PMID: 11606101, 27433846, 28152038, 15131399, 24094589, 30720243, 25849179, 12048272, 28888541, 30787465, 34717758, 29922827)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000522313	SCV000887888	pathogenic	not provided	2024-11-06	criteria provided, single submitter	clinical testing	The BRCA2 c.6757_6758del (p.Leu2253Phefs*7) 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 (PMID: 34717758 (2021), 29337092 (2018), 11606101 (2001)), and an individual with prostate cancer (PMID: 27433846 (2016)). The frequency of this variant in the general population, 0.000004 (1/251352 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000162933	SCV000906927	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-29	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 prostate cancer, breast cancer, and/or ovarian cancer (PMID: 11606101, 27433846, 29337092, 34717758). This variant has been identified in 6 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/251352 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	RCV000045041	SCV000918813	pathogenic	Hereditary breast ovarian cancer syndrome	2020-12-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6757_6758delCT (p.Leu2253PhefsX7) 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 4e-06 in 251352 control chromosomes. c.6757_6758delCT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000522313	SCV002050065	pathogenic	not provided	2020-12-04	criteria provided, single submitter	clinical testing	The BRCA2 c.6757_6758del; p.Leu2253PhefsTer7 variant (rs80359623), also known as 6985delCT in traditional nomenclature, is reported in the literature in individuals and families with hereditary cancer (Lubinski 2004, Pritchard 2016, Schorge 2001). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 52177) 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 2 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: Lubinski J et al. Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer. 2004;3(1):1-10. Pritchard et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Schorge et al. Germline BRCA1-2 mutations in non-Ashkenazi families with double primary breast and ovarian cancer. Gynecol Oncol. 2001 Nov;83(2):383-7.
Revvity Omics, Revvity	RCV000522313	SCV003813717	pathogenic	not provided	2022-10-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473388	SCV004210392	pathogenic	Familial cancer of breast	2023-02-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004803876	SCV005424550	pathogenic	BRCA2-related cancer predisposition	2024-03-24	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 prostate cancer, breast cancer, and/or ovarian cancer (PMID: 11606101, 27433846, 29337092, 34717758). This variant has been identified in 6 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/251352 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV004803876	SCV005919942	pathogenic	BRCA2-related cancer predisposition	2022-09-29	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113638	SCV000146924	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113638	SCV000297548	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-01-13	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000045041	SCV000587868	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research