Submissions for variant NM_000059.4(BRCA2):c.1800T>G (p.Tyr600Ter)

dbSNP: rs80358464

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077266	SCV000300463	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.
Ambry Genetics	RCV000162912	SCV000213399	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-01	criteria provided, single submitter	clinical testing	The p.Y600* pathogenic mutation (also known as c.1800T>G), located in coding exon 9 of the BRCA2 gene, results from a T to G substitution at nucleotide position 1800. This changes the amino acid from a tyrosine to a stop codon within coding exon 9. The p.Y600* nonsense alteration resulting from a different substitution at the same nucleotide position (c.1800T>A, also denoted T2028A in the published literature) has been identified in two African American and one European breast/ovarian cohorts (Pal T et al. Breast J. 2013 Mar-Apr;19(2):189-92; Tea MK et al. Maturitas. 2014 Jan;77(1):68-72; Lynce F et al. Breast Cancer Res. Treat. 2015 Aug;153(1):201-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077266	SCV000267747	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077266	SCV000326615	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000418517	SCV000517273	pathogenic	not provided	2023-10-18	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2028T>G; This variant is associated with the following publications: (PMID: 23320992, 28281021, 26250392, 24156927, 31411802, 32377563, 28888541, 33206196, 29446198)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000418517	SCV000600489	pathogenic	not provided	2017-03-07	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496768	SCV000605810	pathogenic	Hereditary breast ovarian cancer syndrome	2016-12-23	criteria provided, single submitter	clinical testing	The p.Tyr600X variant in BRCA2 has been reported in at least 3 individuals with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database) and was absent from large population studies. This nonsense variant leads to a prematur e termination codon at position 600, which is predicted to lead to a truncated o r absent protein. Heterozygous loss of function of the BRCA2 gene is an establis hed disease mechanism in hereditary breast and ovarian cancer (HBOC). In additio n, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen -approved ENIGMA expert panel (ClinVar SCV000300463.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein.
Color Diagnostics, LLC DBA Color Health	RCV000162912	SCV000905004	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-18	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 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 observed in individuals affected with breast cancer (PMID: 23320992, 26250392). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496768	SCV001591923	pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-24	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 51199). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 23320992, 26250392). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr600*) 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). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000418517	SCV003814970	pathogenic	not provided	2022-04-27	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077266	SCV000109063	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077266	SCV000145943	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496768	SCV000587611	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research