Submissions for variant NM_000059.4(BRCA2):c.4111C>T (p.Gln1371Ter)

dbSNP: rs80358659

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)	RCV000077320	SCV000300708	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	RCV000044353	SCV000072366	pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1371*) 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 cancer (PMID: 25371446). ClinVar contains an entry for this variant (Variation ID: 51599). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131073	SCV000186003	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-14	criteria provided, single submitter	clinical testing	The p.Q1371* pathogenic mutation (also known as c.4111C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 4111. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This alteration was detected in three individuals from a cohort of 810 unselected, Hispanic women with a personal history of breast cancer (Torres-Mejía G et al. Cancer Epidemiol. Biomarkers Prev. 2015 Mar;24:498-505). 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	RCV000478066	SCV000296507	pathogenic	not provided	2021-03-12	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been identified in individuals affected with breast cancer in the published literature (PMID: 29446198 (2018), 26564481 (2015), 25371446 (2014), 17319787 (2007)). 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	RCV000077320	SCV000326972	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000478066	SCV000567705	pathogenic	not provided	2024-01-26	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 BRCA2-related cancers (PMID: 11056688, 22711857, 26564481, 25371446); 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 4339C>T; This variant is associated with the following publications: (PMID: 26564481, 28127413, 22711857, 10923033, 25371446, 11056688, 26295337, 17319787, 29446198, 30787465, 36367610, 35438911)
Color Diagnostics, LLC DBA Color Health	RCV000131073	SCV000688849	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-14	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: 25371446) and ovarian cancer (PMID: 22711857). 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	RCV000044353	SCV000694744	pathogenic	Hereditary breast ovarian cancer syndrome	2021-09-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4111C>T (p.Gln1371X) 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 was absent in 248174 control chromosomes. c.4111C>T has been widely reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_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. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000478066	SCV001158451	pathogenic	not provided	2024-07-24	criteria provided, single submitter	clinical testing	The BRCA2 c.4111C>T; p.Gln1371Ter variant (rs80358659; ClinVar Variation ID: 51599) has been described in multiple individuals and families affected with hereditary breast and ovarian cancer (HBOC; Rebbeck 2018, Torres-Mejia 2015). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant induces an early termination codon in exon 11 (of 27) and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in association with HBOC (Rebbeck 2018). Based on available information, the p.Gln1371Ter variant is considered pathogenic. REFERENCES Rebbeck T et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. Torres-Mejia G et al. Recurrent BRCA1 and BRCA2 mutations in Mexican women with breast cancer. Cancer Epidemiol Biomarkers Prev. 2015 Mar;24(3):498-505.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310148	SCV001499726	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473335	SCV004211929	pathogenic	Familial cancer of breast	2023-11-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077320	SCV004845275	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-04	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: 25371446) and ovarian cancer (PMID: 22711857). 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.
Sharing Clinical Reports Project (SCRP)	RCV000077320	SCV000109117	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-01-24	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077320	SCV000146376	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1998-02-06	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044353	SCV000587699	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332099	SCV004040501	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research