Submissions for variant NM_000059.4(BRCA2):c.8575C>T (p.Gln2859Ter)

dbSNP: rs80359115

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113964	SCV000301291	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	RCV000045563	SCV000073576	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln2859*) 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 male breast cancer and a personal and/or family history of breast and/or ovarian cancer (PMID: 18779604, 20927582). ClinVar contains an entry for this variant (Variation ID: 52626). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000113964	SCV000296663	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-06-03	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113964	SCV000327927	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000483527	SCV000566284	pathogenic	not provided	2016-09-20	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA2 c.8575C>T at the cDNA level and p.Gln2859Ter (Q2859X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in patients with a personal and/or family history of breast/or ovarian cancer, including an individual with male breast cancer (Kurian 2008, Lee 2008, Ding 2011). We consider this variant to be pathogenic.
Ambry Genetics	RCV000509703	SCV000608264	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-06	criteria provided, single submitter	clinical testing	The p.Q2859* pathogenic mutation (also known as c.8575C>T), located in coding exon 19 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8575. This changes the amino acid from a glutamine to a stop codon within coding exon 19. This mutation has been detected in a female early-onset breast cancer patient (Lee E et al. Breast Cancer Res, 2008 Feb;10:R19), as well as male breast cancer patients (Ding YC et al. Breast Cancer Res Treat, 2011 Apr;126:771-8; Pritzlaff M et al. Breast Cancer Res Treat, 2017 02;161:575-586). This mutation was detected in a patient with renal cancer with a family history of renal, breast, pancreatic and other cancers (Hartman TR et al. Sci Rep, 2020 08;10:13518). Additionally, this mutation was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). 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.
Color Diagnostics, LLC DBA Color Health	RCV000509703	SCV000683985	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 20 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	RCV003473425	SCV004212875	pathogenic	Familial cancer of breast	2021-11-29	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113964	SCV000147405	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113964	SCV000297569	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-12-26	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000045563	SCV000587962	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research