ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7878G>A (p.Trp2626Ter) (rs80359013)

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Total submissions: 12
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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) RCV000031706 SCV000301216 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 RCV000045335 SCV000073348 pathogenic Hereditary breast and ovarian cancer syndrome 2020-04-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp2626*) 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 individual(s) with hereditary breast and ovarian cancer (PMID: 22970155, 25452441, 21218378, 26187060). This variant is also known as 8106G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 38124). 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 RCV000217125 SCV000276739 pathogenic Hereditary cancer-predisposing syndrome 2019-03-08 criteria provided, single submitter clinical testing The p.W2626* pathogenic mutation (also known as c.7878G>A) located in coding exon 16 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7878. This changes the amino acid from a tryptophan to a stop codon within coding exon 16. This alteration has been reported in multiple high-risk breast and/or ovarian cancer patients in the literature (Carney ME et al. Hawaii Med J. 2010 Nov;69:268-71; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Kwong A et al. PLoS ONE. 2012 Sep;7:e43994; Kwong A et al. J. Med. Genet. 2016 Jan;53:15-23; Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). 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 RCV000237084 SCV000293484 pathogenic not provided 2017-06-11 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7878G>A at the cDNA level and p.Trp2626Ter (W2626X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also defined as BRCA2 8106G>A using alternate nomenclature, has been reported in association with breast and/or ovarian cancer (Carney 2010, Kwong 2012, Couch 2015) and is considered pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031706 SCV000327754 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031706 SCV000489210 pathogenic Breast-ovarian cancer, familial 2 2016-09-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045335 SCV000695105 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-09 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7878G>A (p.Trp2626*) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g. c.7900delA (p.Met2634fsX14), c.7908T>A (p.C2636*) and c.7934delG (p.Arg2645fsX3)). This variant is absent in 121350 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic.
Color Health, Inc RCV000217125 SCV000906563 pathogenic Hereditary cancer-predisposing syndrome 2020-10-06 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 17 of the BRCA2 gene, creating a 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 multiple individuals affected with breast cancer (PMID: 21218378, 25452441, 26187060) and one individual who also had cancer of the brain (PMID: 21218378). 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.
Sharing Clinical Reports Project (SCRP) RCV000031706 SCV000054313 pathogenic Breast-ovarian cancer, familial 2 2013-03-12 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031706 SCV000147207 uncertain significance Breast-ovarian cancer, familial 2 2013-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045335 SCV000587917 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353668 SCV000592154 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Trp2626X variant was identified in 6 of 1438 proband chromosomes (frequency: 0.004) from multiethnic Asian individuals or families with high risk breast cancer; the variant being frequent in the Hong Kong population (Kwong 2012, Kwong 2015). The variant was also identified in dbSNP (ID: rs80359013) “With Pathogenic” allele, ClinVar (classified as pathogenic, reviewed by expert panel; submitters: ENIGMA, Counsyl, Invitae, Ambry Genetics, GeneDx, SCRP and CIMBA), Clinvitae (4x), BIC Database (1x, with unknown clinical importance, class 3-uncertain significance), and ARUP Laboratories (5-definitely pathogenic). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The variant was also identified by our laboratory in 3 individuals at risk of familial breast cancer. The p.Trp2626X variant leads to a premature stop codon at position 2626, which is predicted to lead to 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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