Submissions for variant NM_000059.4(BRCA2):c.2095C>T (p.Gln699Ter)

dbSNP: rs878853559

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000256526	SCV000324047	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229702	SCV000283182	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln699*) 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: 23683081). ClinVar contains an entry for this variant (Variation ID: 236835). For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000256526	SCV000326655	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000482408	SCV000566006	pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA2 c.2095C>T at the cDNA level and p.Gln699Ter (Q699X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also defined as BRCA2 2323C>T using alternate nomenclature, has been reported in breast and ovarian cancer families (Blay 2013) and is considered pathogenic.
Yang An-Suei Laboratory, Academia Sinica	RCV000494713	SCV000583411	pathogenic	Breast neoplasm		criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482408	SCV000600500	pathogenic	not provided	2016-09-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000510002	SCV000608277	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-20	criteria provided, single submitter	clinical testing	The p.Q699* pathogenic mutation (also known as c.2095C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 2095. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This alteration has been identified in multiple high-risk breast and/or ovarian cancer families (Blay P et al. BMC Cancer 2013; 13:243; Gabaldo Barrios X et al. Fam Cancer. 2017 Oct;16(4):477-489; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Wang YA et al. BMC Cancer, 2018 03;18:315; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Ben Ayed-Guerfali D et al. J Transl Med, 2021 03;19:108; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). 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.
Color Diagnostics, LLC DBA Color Health	RCV000510002	SCV000905235	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-19	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 individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 23683081, 29566657). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000229702	SCV000917044	pathogenic	Hereditary breast ovarian cancer syndrome	2018-10-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2095C>T (p.Gln699X) 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. The variant was absent in 245908 control chromosomes (gnomAD). The variant, c.2095C>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Blay_2013, Wang_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. Six 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.
Baylor Genetics	RCV003475054	SCV004211821	pathogenic	Familial cancer of breast	2023-10-23	criteria provided, single submitter	clinical testing
Center of Medical Genetics and Primary Health Care	RCV000256526	SCV000987242	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria The BRCA2 variant p.Gln699Ter is a known pathogenic variant in exon 11 in a non-functional domain. This nonsense variant truncates the protein and thus makes in non-functional which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This variant was observed in a mutation hotspot region of 14 pathogenic variants (source, ClinVar) (PM1 Pathogenic Moderate). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000324047.1) (PP5 Pathogenic Supporting). In this study this deleterious variant was found in a 30-year-old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000482408	SCV001553523	uncertain significance	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000256526	SCV002588856	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000256526	SCV005061314	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-05-24	no assertion criteria provided	case-control