Submissions for variant NM_000059.4(BRCA2):c.8247_8248del (p.Lys2750fs)

dbSNP: rs80359701

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077432	SCV000282456	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045461	SCV000073474	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys2750Aspfs*13) 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 personal and/or family history of breast/ovarian cancer (PMID: 15340362, 22762150). This variant is also known as 8475delGA. ClinVar contains an entry for this variant (Variation ID: 52536). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162938	SCV000213425	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	The c.8247_8248delGA pathogenic mutation, located in coding exon 17 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 8247 to 8248, causing a translational frameshift with a predicted alternate stop codon (p.K2750Dfs*13). This alteration has been identified in multiple high-risk breast/ovarian cancer families (Marroni, F et al. Eur J Hum Genet. 2004 Nov;12(11):899-906; Musolino, A et al. Breast. 2007 Jun;16(3):280-92; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817). This variant has also been report in 2/81 male breast cancer patients who had multi-gene panel testing (Scarpitta R et al. Breast Cancer Res Treat, 2019 Dec;178:557-564). Of note, this mutation is also designated as 8475delGA. 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	RCV000413191	SCV000296618	pathogenic	not provided	2020-05-01	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals and families with breast cancer in the published literature (PMID: 22762150 (2012) and 15340362 (2004)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077432	SCV000327844	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000413191	SCV000490436	pathogenic	not provided	2021-12-15	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 (Lek 2016); Reported in individuals with personal or family history of BRCA2-related cancers (Marroni 2004, Lecarpentier 2012, Maxwell 2016, Rizzolo 2019, Toss 2019, Darst 2021); Also known as c.8246_8247delAG or 8475_8476delGA; This variant is associated with the following publications: (PMID: 15340362, 22762150, 30787465, 27153395, 30736435, 30613976, 32853339)
Color Diagnostics, LLC DBA Color Health	RCV000162938	SCV001340979	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 18 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 at least 5 individuals affected with breast and/or ovarian cancer, including 1 male individual and 1 individual affected with both breast and ovarian cancer, (PMID: 11879560, 17257844, 22776961, 27163896, 34072659) and has been identified in 36 families among the CIMBA participants (PMID: 29446198). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045461	SCV002512017	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8247_8248delGA (p.Lys2750AspfsX13) 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 was absent in 249060 control chromosomes. c.8247_8248delGA 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. Five clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics Program, Instituto Nacional de Cancer	RCV000045461	SCV002515151	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149694	SCV003838180	pathogenic	Breast and/or ovarian cancer	2022-05-09	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV003313773	SCV004012920	pathogenic	Diffuse midline glioma, H3 K27-altered	2018-05-31	criteria provided, single submitter	research
Baylor Genetics	RCV003473418	SCV004211825	pathogenic	Familial cancer of breast	2023-10-22	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077432	SCV000109230	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-30	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077432	SCV000147309	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	RCV000045461	SCV000587942	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research