Submissions for variant NM_000059.4(BRCA2):c.8229_8243del (p.Arg2744_Gly2748del)

dbSNP: rs80359698

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129438	SCV000184208	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-11-01	criteria provided, single submitter	clinical testing	The c.8229_8243del15 variant (also known as p.R2744_G2748del) is located in coding exon 17 of the BRCA2 gene. This variant results from an in-frame CAGACTGACAGTTGG deletion at nucleotide positions 8229 to 8243. This results in the in-frame deletion of five amino acids at codons 2744 to 2748. This alteration (designated as 8457del15) was first reported in an ovarian cancer patient diagnosed at age 50 and was shown to segregate with disease in this family (Martinez SL et al. J Med Genet, 2004 Feb;41:e18). In a large, clinic-based BRCA1/2 testing cohort in Norway, this variant was detected in five families (Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3). This amino acid region is well conserved in available vertebrate species, and is part of the OB1 domain, a region that has been designated as critical for protein function (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Department of Medical Genetics, Oslo University Hospital	RCV000113891	SCV000605683	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-05-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758956	SCV000887933	likely pathogenic	not provided	2021-03-03	criteria provided, single submitter	clinical testing	This variant has been reported in multiple families with hereditary breast and/or ovarian cancer in the published literature (PMID: 14757868 (2004), 18284688 (2008), 29339979 (2018)). It was not found in a large general population data set (Genome Aggregation Database (http://gnomad.broadinstitute.org/)). The variant has been reported to segregate with disease, and tumor tissue from affected individuals showed loss of the wild type BRCA2 allele (PMID: 14757868 (2004)). The variant results in the in-frame deletion of five amino acids in the DNA/DSS1 binding domain of the BRCA2 protein, which has been characterized as evolutionarily highly conserved and functionally significant (PMID: 14757868 (2004)). Analysis of this variant using a bioinformatics tool for the prediction of the effect of amino acid changes on protein structure and function yielded the prediction that this variant is disease causing. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on BRCA2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Variant is located in potentially critical domain of the protein. Based on the available information, we predict that the variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001301984	SCV001491171	pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-10	criteria provided, single submitter	clinical testing	This variant, c.8229_8243del, results in the deletion of 5 amino acid(s) of the BRCA2 protein (p.Arg2744_Gly2748del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer (PMID: 14757868, 29339979). This variant is also known as 8457del15. ClinVar contains an entry for this variant (Variation ID: 52531). RNA analysis performed to evaluate the impact of this variant on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Gly2748Asp) have been determined to be pathogenic (PMID: 15026808, 17924331, 22711857, 23108138, 23328489, 25146914). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV004566849	SCV005058340	likely pathogenic	Familial cancer of breast	2024-03-28	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113891	SCV000147303	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	flagged submission	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000257933	SCV000324856	uncertain significance	Breast and/or ovarian cancer	2016-01-26	flagged submission	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496772	SCV000587940	uncertain significance	not specified	2014-01-31	flagged submission	research