ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1054dup (p.Tyr352fs) (rs80359261)

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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) RCV000031306 SCV000300383 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000130964 SCV000185879 pathogenic Hereditary cancer-predisposing syndrome 2018-05-09 criteria provided, single submitter clinical testing The c.1054dupT pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a duplication of T at nucleotide position 1054, causing a translational frameshift with a predicted alternate stop codon (p.Y352Lfs*6). This mutation has been reported multiple individuals with breast cancer <span style="font-family:arial,helvetica,sans-serif"><span style="font-size:12px">(Rashidi A et al. Med. Oncol. 2015 Jan;32:371; Maxwell KN et al. Nat. Commun. 2017 08;8(1):319). 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768618 SCV000324884 pathogenic Breast and/or ovarian cancer 2015-08-12 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031306 SCV000326488 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000365830 SCV000329132 pathogenic not provided 2018-04-11 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA2 is denoted c.1054dupT at the cDNA level and p.Tyr352LeufsX6 (Y352LfsX6) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GAAAAA[dupT]ACTC. The duplication causes a frameshift which changes a Tyrosine to a Leucine at codon 352, and creates a premature stop codon at position 6 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.1054dupT, also denoted BRCA2 1282insT using alternate nomenclature, has been reported in the literature in several individuals with a personal and/or family history of breast and/or ovarian cancer (Sinclair 2002, Rashidi 2015, Dos Santos Vidal 2016, Maxwell 2017). We consider this variant to be pathogenic.
Invitae RCV000257966 SCV000549801 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr352Leufs*6) 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 reported in several individuals with a personal and/or family history of breast and/or ovarian cancer. (PMID: 25428384, 26941049, 28831036). This variant is also known as 1282insT in the literature. ClinVar contains an entry for this variant (Variation ID: 37725). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Molecular Medicine,Queen's University RCV000257966 SCV000588076 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Counsyl RCV000031306 SCV000677668 likely pathogenic Breast-ovarian cancer, familial 2 2016-12-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130964 SCV000903408 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000365830 SCV001716143 pathogenic not provided 2021-01-05 criteria provided, single submitter clinical testing PVS1, PM2, PP4, PP5
Sharing Clinical Reports Project (SCRP) RCV000031306 SCV000053911 pathogenic Breast-ovarian cancer, familial 2 2008-11-20 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031306 SCV000145811 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000257966 SCV000587579 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356465 SCV001551642 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Tyr352Leufs*6 variant was identified in 6 of 61698 proband chromosomes (frequency: 0.0001) from individuals or families with breast or ovarian cancer (Dos Santos Vidal 2016, Maxwell 2017, Rebbeck 2018). The variant was also identified in dbSNP (ID: rs80359261) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and seven other submitters; as likely pathogenic by Counsyl), and LOVD 3.0 (2x as pathogenic). The variant was not identified in the UMD-LSDB database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.1054dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 352 and leads to a premature stop codon at position 357. 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 (HBOC) 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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