Submissions for variant NM_000059.4(BRCA2):c.5655C>A (p.Cys1885Ter)

dbSNP: rs80358789

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031566	SCV000300913	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000044709	SCV000072722	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys1885*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 37985). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000160093	SCV000210360	pathogenic	not provided	2017-05-24	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA2 c.5655C>A at the cDNA level and p.Cys1885Ter (C1885X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 5883C>A. The substitution creates a nonsense variant, changing a Cysteine to a premature stop codon (TGC>TGA). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not been previously reported the literature to our knowledge, it is considered pathogenic.
Ambry Genetics	RCV000220539	SCV000278194	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-09	criteria provided, single submitter	clinical testing	The p.C1885* pathogenic mutation (also known as c.5655C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 5655. This changes the amino acid from a cysteine to a stop codon within coding exon 10. This mutation has been identified in a female patient with breast cancer (Tung N et al. Cancer. 2015 Jan 1;121(1):25-33). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160093	SCV000296708	pathogenic	not provided	2019-09-16	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 patient with expected phenotype for this gene, and not found in general population data.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031566	SCV000327255	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220539	SCV000905016	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least one individual affected with breast cancer (PMID: 25186627) and has been identified in 3 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044709	SCV000916955	pathogenic	Hereditary breast ovarian cancer syndrome	2018-04-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5655C>A (p.Cys1885X) 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 (eg. c.5656C>T, p.Gln1886X; c.5681dupA, p.Tyr1894X; c.5682C>G, p.Tyr1894X). The variant was absent in 30948 control chromosomes (gnomAD). The variant, c.5655C>A, has been reported in the literature in one individual affected with Hereditary Breast and Ovarian Cancer (Tung_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000160093	SCV002048503	pathogenic	not provided	2021-05-29	criteria provided, single submitter	clinical testing	The BRCA2 c.5655C>A; p.Cys1885Ter variant (rs80358789) is reported in several individuals and families with hereditary breast and ovarian cancer (Rebbeck 2018, Tung 2015). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37985) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and 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: Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. PMID: 2944619. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. PMID: 25186627.
Sharing Clinical Reports Project (SCRP)	RCV000031566	SCV000054171	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031566	SCV000146657	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044709	SCV000587787	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research