ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5303_5304del (p.Leu1768fs) (rs80359505)

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Total submissions: 14
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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) RCV000031538 SCV000300858 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 RCV000074536 SCV000072646 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1768Argfs*5) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80359505, ExAC 0.002%). This particular variant has been reported in the literature in individuals and families affected with breast and/or ovarian cancer, and prostate cancer (PMID: 21895635, 22762150, 10969800). This variant is also known as 5531delTT in the literature. ClinVar contains an entry for this variant (Variation ID: 37957). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000235139 SCV000108621 pathogenic not provided 2018-04-16 criteria provided, single submitter clinical testing This deletion of two nucleotides is denoted BRCA2 c.5303_5304delTT at the cDNA level and p.Leu1768ArgfsX5 (L1768RfsX5) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAAC[delTT]GATT. The deletion causes a frameshift, which changes a Leucine to an Arginine at codon 1768, and creates a premature stop codon at position 5 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 5303_5304delTT, previously reported as 5531delTT, has been observed in individuals with personal and/or family histories of breast, ovarian, and/or prostate cancer (Gayther 2000, Gutierrez Espeleta 2012, Song 2014). We consider this variant to be pathogenic
Ambry Genetics RCV000162923 SCV000213410 pathogenic Hereditary cancer-predisposing syndrome 2017-08-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031538 SCV000327196 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Color RCV000162923 SCV000683693 pathogenic Hereditary cancer-predisposing syndrome 2017-05-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000074536 SCV000694857 pathogenic Hereditary breast and ovarian cancer syndrome 2019-04-16 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5303_5304delTT (p.Leu1768ArgfsX5) 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 (c.5471dupA, p.Asn1824fsX5; c.5576_5579delTTAA, p.Ile1859fsX3; c.5682C>G, p.Tyr1894X). The variant allele was found at a frequency of 4e-06 in 250376 control chromosomes (gnomAD and one publication). The variant, c.5303_5304delTT, has been reported in the literature in multiple individuals affected with breast and ovarian cancer (Espeleta_2012, Tea_2014, Kraus_2016, Rebbeck_2018). 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. Eight ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics RCV000074536 SCV000838813 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235139 SCV000889060 pathogenic not provided 2018-06-25 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002437 SCV001160374 pathogenic not specified 2019-03-05 criteria provided, single submitter clinical testing The BRCA2 c.5303_5304delTT; p.Leu1768fs variant (rs80359505), also known as 5531delTT, is reported in the literature in individuals and families affected with breast, ovarian, or prostate cancer (Castro 2013, Gayther 2000, Gutierrez Espeleta 2012, Kraus 2017, Tea 2014). In at least one family, this variant was observed in multiple individuals affected with breast cancer (Gutierrez Espeleta 2012). This variant is found on only one chromosome in the Genome Aggregation Database (1/250376 alleles), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37957). 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: Castro E et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013 May 10;31(14):1748-57. Gayther SA et al. The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. Cancer Res. 2000 Aug 15;60(16):4513-8. Gutierrez Espeleta GA et al. BRCA1 and BRCA2 mutations among familial breast cancer patients from Costa Rica. Clin Genet. 2012 Nov;82(5):484-8. Kraus C et al. Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Int J Cancer. 2017 Jan 1;140(1):95-102. Tea MK et al. Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer. Maturitas. 2014 Jan;77(1):68-72.
Sharing Clinical Reports Project (SCRP) RCV000031538 SCV000054143 pathogenic Breast-ovarian cancer, familial 2 2012-07-10 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031538 SCV000146596 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Division Human Genetics,Medical University Innsbruck RCV000031538 SCV000212020 pathogenic Breast-ovarian cancer, familial 2 2015-02-11 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000074536 SCV000587759 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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