ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5851_5854del (rs80359543)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031582 SCV000300941 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000044773 SCV000072786 pathogenic Hereditary breast and ovarian cancer syndrome 2020-08-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser1951Trpfs*11) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with breast and/or ovarian cancer (PMID: 22752604, 22970155, 18821011, 26183948, 19805903, 29335924, 29487695, 27882536). This variant is also known as 6079delAGTT in the literature. ClinVar contains an entry for this variant (Variation ID: 38001). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131116 SCV000186046 pathogenic Hereditary cancer-predisposing syndrome 2018-12-12 criteria provided, single submitter clinical testing The c.5851_5854delAGTT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5851 to 5854, causing a translational frameshift with a predicted alternate stop codon (p.S1951Wfs*11). This mutation has been reported in multiple breast and/or ovarian cancer families across various ethnicities (Vaidyanathan K et al. J. Biosci. 2009 Sep;34:415-22; Papi L et al. Breast Cancer Res. Treat. 2009 Oct;117:497-504; Kwong A et al. Breast Cancer Res. Treat. 2009 Oct;117:683-6; Juwle A et al. Med. Oncol. 2012 Dec;29:3272-81; Dodova RI et al. BMC Cancer. 2015 Jul;15:523; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24(2):326-333; Jakimovska M et al. Breast Cancer Res. Treat. 2018 Apr;168(3):745-753). Of note, this alteration is also designated as 6079_6082delAGTT and 6079delAGTT in published literature. 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 RCV000254645 SCV000210772 pathogenic not provided 2016-11-09 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.5851_5854delAGTT at the cDNA level and p.Ser1951TrpfsX11 (S1951WfsX11) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TGTT[delAGTT]TGGA. The deletion causes a frameshift, changing a Serine to a Tryptophan at codon 1951, and creates a premature stop codon at position 11 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.5851_5854delAGTT, also reported as 6079del4 or 6079_6082delAGTT using alternate nomenclature, has been seen in association with breast and/or ovarian cancer (Díez 2003, Kwong 2009, Papi 2009, Vaidyanathan 2009, Juwle 2012, Dodova 2015). We consider this variant to be pathogenic.
Counsyl RCV000031582 SCV000220670 likely pathogenic Breast-ovarian cancer, familial 2 2014-09-04 criteria provided, single submitter literature only
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031582 SCV000327297 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254645 SCV000600665 pathogenic not provided 2017-02-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131116 SCV000688951 pathogenic Hereditary cancer-predisposing syndrome 2020-10-22 criteria provided, single submitter clinical testing This variant deletes 4 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 12955716, 18821011, 25186627, 26183948, 27153395, 27882536, 29487695, 29335924, 29470806, 30430080). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000254645 SCV000883482 pathogenic not provided 2017-05-17 criteria provided, single submitter clinical testing The BRCA2 c.5851_5854delAGTT; p.Ser1951fs variant (also known as 6079delAGTT) has been reported in several individuals with hereditary breast and ovarian cancer syndrome (Dodova 2015, Juwle 2012, Kwong 2012, Papi 2009, Vaidyanathan 2009). This variant is reported in ClinVar (Variation ID: 38001), and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). This variant creates a frameshift and is predicted to result in a truncated protein or absent transcript, and is considered pathogenic. REFERENCES Link to ClinVar database for c.5851_5854delAGTT: https://www.ncbi.nlm.nih.gov/clinvar/variation/38001/ Dodova RI et al. Spectrum and frequencies of BRCA1/2 mutations in Bulgarian high risk breast cancer patients. BMC Cancer. 2015 Jul 17;15:523. Juwle A et al. BRCA1/BRCA2 gene mutations/SNPs and BRCA1 haplotypes in early-onset breast cancer patients of Indian ethnicity. Med Oncol. 2012 Dec;29(5):3272-81. Kwong A et al. Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis. PLoS One. 2012;7(9):e43994. Papi L et al. Founder mutations account for the majority of BRCA1-attributable hereditary breast/ovarian cancer cases in a population from Tuscany, Central Italy. Breast Cancer Res Treat. 2009 Oct;117(3):497-504. Vaidyanathan K et al. BRCA1 and BRCA2 germline mutation analysis among Indian women from south India: identification of four novel mutations and high-frequency occurrence of 185delAG mutation. J Biosci. 2009 Sep;34(3):415-22.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000254645 SCV001450202 pathogenic not provided 2016-09-30 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001310126 SCV001499674 pathogenic Breast-ovarian cancer, familial 1 2020-04-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031582 SCV000054188 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031582 SCV000146713 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044773 SCV000587804 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000031582 SCV000592005 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.Ser1951TrpfsX11 variant was identified in 9 of 3458 proband chromosomes (frequency: 0.008) from individuals with breast cancer or hereditary breast and ovarian cancer families (Diez 2003 12955716, Juwle 2012, Kurian 2008, Lubinski 2004, Papi 2009, Vaidyanathan 2009). The variant was not detected in 500 control chromosomes from healthy individuals from these studies. The variant was also identified in dbSNP (ID: rs80359543), LOVD, UMD (6X as a causal variant), and the BIC database (11X with clinical importance). The p.Ser1951TrpfsX11 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1951and leads to a premature stop codon 11 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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