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

gnomAD frequency: 0.00001  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)	RCV000031340	SCV000300462	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	RCV000131060	SCV000185990	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-25	criteria provided, single submitter	clinical testing	The p.Y600* pathogenic mutation (also known as c.1800T>A), located in coding exon 9 of the BRCA2 gene, results from a T to A substitution at nucleotide position 1800. This changes the amino acid from a tyrosine to a stop codon within coding exon 9. This alteration has been reported in individuals diagnosed with breast cancer and prostate cancer (Pal T et al. Breast J. 2013 Mar-Apr;19:189-92; Tea MK et al. Maturitas. 2014 Jan;77:68-72; Lynce F et al. Breast Cancer Res. Treat. 2015 Aug;153:201-9; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as Y600X and 2028T>A in published literature. 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	RCV000216426	SCV000279312	pathogenic	not provided	2024-04-26	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 23320992, 24156927, 26250392); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2028T>A; This variant is associated with the following publications: (PMID: 24156927, 26250392, 23320992, 29446198, 31411802, 31447099, 32832836, 33206196)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031340	SCV000326614	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000216426	SCV000600488	pathogenic	not provided	2016-11-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496257	SCV000694567	pathogenic	Hereditary breast ovarian cancer syndrome	2016-05-09	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.1800T>A (p.Tyr600X) 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. p.Glu1518fsX25, p.Thr1526fsX3, p.Tyr1655X, etc.). One in silico tool predicts a damaging outcome for this variant. This variant was absent in 118492 control chromosomes, but has been cited in multiple HBOC patients in the literature. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496257	SCV000814370	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-12	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 23320992, 24156927, 26250392). This variant is also known as T2028A or 2028T>A. ClinVar contains an entry for this variant (Variation ID: 37759). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031340	SCV000839917	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-24	criteria provided, single submitter	clinical testing	This c.1800T>A (p.Tyr600*) variant in the BRCA2 gene has been reported in patients with breast cancer [PMID 26250392, 23320992]. This variant is predicted to create a non sense variant and a premature stop codon at amino acid position 600 of the BRCA2 protein. This variant is thus predicted to result in a loss of function of the protein. In addition, it has been classified as pathogenic in ClinVar by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/37759/). This variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131060	SCV000905003	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	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 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.
Baylor Genetics	RCV003460500	SCV004213714	pathogenic	Familial cancer of breast	2023-08-02	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031340	SCV000053945	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-31	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031340	SCV000145942	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	RCV000496257	SCV000587612	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research