ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5146_5149del (p.Tyr1716fs) (rs276174854)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214399 SCV000276555 pathogenic Hereditary cancer-predisposing syndrome 2017-05-26 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)
Breast Cancer Information Core (BIC) (BRCA2) RCV000113387 SCV000146547 pathogenic Breast-ovarian cancer, familial 2 2005-01-26 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113387 SCV000327140 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000456131 SCV000591944 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-26 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000113387 SCV000300833 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000044567 SCV000210760 pathogenic not provided 2019-01-22 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.5146_5149delTATG at the cDNA level and p.Tyr1716LysfsX8 (Y1716KfsX8) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TTTG[delTATG]AAAAT. The deletion causes a frameshift, which changes a Tyrosine to a Lysine at codon 1716, and creates a premature stop codon at position 8 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 5146_5149delTATG, previously reported as 5374del4 or 5373del4 using alternate nomenclature, has been observed in association with breast and ovarian cancer and is a founder pathogenic variant in populations of Spanish ancestry (Llort 2002, Infante 2010, Gonzalez-Hormazabal 2011, de Juan Jimenez 2013, de Juan 2015). We therefore consider this variant to be pathogenic.
Genologica Medica RCV000113387 SCV000577954 pathogenic Breast-ovarian cancer, familial 2 2017-01-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000456131 SCV000694832 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-31 criteria provided, single submitter clinical testing Variant summary: The c.5146_5149delTATG (p.Tyr1716Lysfs) variant in BRCA2 gene is a frame shift predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The variant has been reported in multiple affected individuals and was shown to segregate with the disease in several families (Infante, 2010). This variant is found in 1/118220 control chromosomes at a frequency of 0.000008, which does not exceed the maximal expected frequency of a pathogenic allele (0.0007503) in this gene. Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic.
Invitae RCV000456131 SCV000072580 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-06 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 11 of the BRCA2 mRNA (c.5146_5149delTATG), causing a frameshift at codon 1716. This creates a premature translational stop signal (p.Tyr1716Lysfs*8) and is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs763933639, ExAC 0.009%). This variant has been reported in the literature in several families affected with breast and ovarian cancer (PMID: 11857748, 23479189, 19912264, 16261400, 20859677), including two individuals affected with male breast cancer (PMID: 26026974). This variant has been reported in the literature as a Spanish founder mutation (PMID: 19912264, 23199084). This variant is also known as 5374delTATG, 5373delGTAT, c.5374_5377delTATG, c.5373_5376delGTAT in the literature. ClinVar contains an entry for this variant (Variation ID: 51779). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

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