ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1689G>A (p.Trp563Ter) (rs80358456)

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Total submissions: 11
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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) RCV000112960 SCV000282358 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000043863 SCV000071876 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 563 (p.Trp563*) of 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 an individual affected with cancer (PMID: 15131399), although the type was not specified. ClinVar contains an entry for this variant (Variation ID: 51175). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112960 SCV000326591 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000112960 SCV000488684 likely pathogenic Breast-ovarian cancer, familial 2 2016-05-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000581281 SCV000688718 pathogenic Hereditary cancer-predisposing syndrome 2020-02-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000043863 SCV000918840 pathogenic Hereditary breast and ovarian cancer syndrome 2018-05-23 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1689G>A (p.Trp563X) 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 (e.g., p.Leu579X and p.Lys585fsX3). The variant allele was found at a frequency of 4.1e-06 in 246026 control chromosomes. c.1689G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985467 SCV001133687 pathogenic not provided 2019-03-15 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Ambry Genetics RCV000581281 SCV001173224 pathogenic Hereditary cancer-predisposing syndrome 2017-12-20 criteria provided, single submitter clinical testing The p.W563* pathogenic mutation (also known as c.1689G>A), located in coding exon 9 of the BRCA2 gene, results from a G to A substitution at nucleotide position 1689. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. 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.
Breast Cancer Information Core (BIC) (BRCA2) RCV000112960 SCV000145920 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 RCV000043863 SCV000587604 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354296 SCV001548877 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Trp563X variant was identified in 1 of 880 proband chromosomes (frequency: 0.001) from individuals or families across several ethnicities with ovarian, male breast, pancreatic, prostate, colon, stomach and melanoma cancers (Lubinski 2004). The variant was also identified in ClinVar as pathogenic by Evidence-based Network for the interpretation of Germline Mutant Alleles, in Consortium of Investigators of Modifiers of BRCA1/2, in Invitae, in Breast Cancer Information Core, and in Research Molecular Genetics Laboratory, Women's College Hospital; and as likely pathogenic by Counsyl and Clinvitae. The variant was also identified 4X in LOVD 3.0 database with a frequency of 0.001, in BIC 6X as Class 5 with clinical importance, and in ARUP Laboratories databases 1X as definitely pathogenic . The variant was identified in dbSNP (ID:rs 80358456) as “with pathogenic allele”, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer databases or in the 1000 Genomes and the NHLBI GO sequencing projects. The variant was identified in control databases in 1 of 246026 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Finnish in 1 of 22280 chromosomes (freq: 0.00005), while the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, and South Asian populations. The c.1689G>A variant leads to a premature stop codon at position 563 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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