Submissions for variant NM_000059.4(BRCA2):c.2224C>T (p.Gln742Ter)

dbSNP: rs80358494

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077273	SCV000300498	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.
GeneDx	RCV000212220	SCV000210456	pathogenic	not provided	2024-03-28	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; 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 2452C>T; This variant is associated with the following publications: (PMID: 28127413, 18284688, 30630528, 34413315, 25525159, 16030099, 26295337, 25716084, 25628955, 27221827, 29446198, 26543556, 29922827, 25371446, 35875314, 31853058, 33293522)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212220	SCV000296604	pathogenic	not provided	2021-07-20	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000029 (1/34534 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer in the published literature (PMID: 30630528 (2019), 29446198 (2018), 26681312 (2015), 26543556 (2015), 25628955 (2015), 16030099 (2005)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077273	SCV000326673	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568409	SCV000661152	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-02	criteria provided, single submitter	clinical testing	The p.Q742* pathogenic mutation (also known as c.2224C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 2224. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This mutation has been observed in multiple Mexican probands with personal and/or family histories of breast and/or ovarian cancer (Weitzel JN et al. Cancer Epidemiol. Biomarkers Prev., 2005 Jul;14:1666-71; Lee E et al. Breast Cancer Res, 2008 Feb;10:R19; Villarreal-Garza C et al, 2015 Apr;150:389-94; Dean M et al. Gigascience, 2015 Nov;4:50; Nahleh Z et al. Am J Cancer Res, 2015 Dec;5:466-71; Cruz-Correa M et al. Hered Cancer Clin Pract, 2017 Jan;15:3; Fernández-Lopez JC et al. Hum Genomics, 2019 01;13:3). This mutation 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). Of note, this alteration is also designated as 2452C>T 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496760	SCV000916834	pathogenic	Hereditary breast ovarian cancer syndrome	2022-02-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2224C>T (p.Gln742X) 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 251260 control chromosomes. c.2224C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, who were mostly of Hispanic origin (examples: Weitzel 2005, Lee 2008, Nahleh 2015, Dean 2015). Nine 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000077273	SCV001190320	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-09-25	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000568409	SCV001355741	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-17	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 five individuals affected with breast cancer (PMID: 18284688, 25628955, 25716084, 26543556, 26681312, 35875314) and in four suspected hereditary breast and ovarian cancer families (PMID: 16030099, 29446198). This variant has been identified in 1/251260 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496760	SCV001586459	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln742*) 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 a personal and/or family history of breast and/or ovarian cancer (PMID: 16030099, 18284688, 25628955, 26543556, 26681312). ClinVar contains an entry for this variant (Variation ID: 51257). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002490602	SCV002800810	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-04-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473311	SCV004210391	pathogenic	Familial cancer of breast	2023-02-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077273	SCV004847023	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-19	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 five individuals affected with breast cancer (PMID: 18284688, 25628955, 25716084, 26543556, 26681312, 35875314) and in four suspected hereditary breast and ovarian cancer families (PMID: 16030099, 29446198). This variant has been identified in 1/251260 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.
Sharing Clinical Reports Project (SCRP)	RCV000077273	SCV000109070	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-02-26	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077273	SCV000146017	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	RCV000496760	SCV000587625	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004732603	SCV000805668	pathogenic	BRCA2-related disorder	2024-03-11	no assertion criteria provided	clinical testing	The BRCA2 c.2224C>T variant is predicted to result in premature protein termination (p.Gln742*). This variant has been reported in patients with breast and/or ovarian cancer (Weitzel et al. 2005. PubMed ID: 16030099; Dean et al. 2015. PubMed ID: 26543556; Rebbeck et al. 2018. PubMed ID: 29446198; Fernández-Lopez et al. 2019. PubMed ID: 30630528). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/) and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51257). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.