Submissions for variant NM_000059.4(BRCA2):c.2376C>A (p.Tyr792Ter)

dbSNP: rs80358503

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)	RCV000077277	SCV000300514	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043981	SCV000071994	pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr792*) 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 present in population databases (rs80358503, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 15876480, 18286383). This variant is also known as 2604C>A. ClinVar contains an entry for this variant (Variation ID: 51274). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131058	SCV000185988	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-16	criteria provided, single submitter	clinical testing	The p.Y792* pathogenic mutation (also known as c.2376C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 2376. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This mutation (designated as 2604C>A) has been identified in a Spanish high-risk breast cancer family (Salazar R et al. Cancer Lett, 2006 Feb;233:172-7). 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	RCV001781369	SCV000296534	pathogenic	not provided	2020-12-05	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast cancer in the published literature (PMID: 29446198 (2018), 18286383 (2008), 15876480 (2006)). Therefore, the variant is classified as pathogenic and this individual is at increased risk of developing BRCA2 related cancers.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077277	SCV000326694	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077277	SCV000488428	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-03-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131058	SCV000906891	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-06	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 15876480, 18286383). This variant has been identified in 1/250538 chromosomes 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	RCV000043981	SCV002041857	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2376C>A (p.Tyr792X) 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. The variant allele was found at a frequency of 4e-06 in 250538 control chromosomes (gnomAD). c.2376C>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome(e.g. Rebbeck_2018, Park_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001781369	SCV002044004	pathogenic	not provided	2023-11-21	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: 15876480, 28888541, 28111427, 29673794); 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 2604C>A; This variant is associated with the following publications: (PMID: 34413315, 15876480, 29446198, 30720243, 25525159, 31589614, 28127413, 18286383, 29673794, 28111427, 28888541, 29922827, 29625052)
Baylor Genetics	RCV003460566	SCV004216180	pathogenic	Familial cancer of breast	2023-04-20	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077277	SCV000109074	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2007-01-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077277	SCV000146035	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2003-05-22	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077277	SCV002588858	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing