Submissions for variant NM_000059.4(BRCA2):c.6206T>G (p.Leu2069Ter)

dbSNP: rs80358859

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031607	SCV000300999	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	RCV000044867	SCV000072880	pathogenic	Hereditary breast ovarian cancer syndrome	2022-09-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 38026). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu2069*) 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).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031607	SCV000327367	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000486394	SCV000569136	pathogenic	not provided	2022-04-29	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Malone 2006, Rebbeck 2018); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 6434T>G; This variant is associated with the following publications: (PMID: 16912212, 9150172, 29446198, 31447099, 30787465)
Ambry Genetics	RCV000568590	SCV000661158	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-27	criteria provided, single submitter	clinical testing	The p.L2069* pathogenic mutation (also known as c.6206T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 6206. This changes the amino acid from a leucine to a stop codon within coding exon 10. A single nucleotide deletion resulting in a stop codon at the same position (p.L2069*) has been identified in a French family with female breast and ovarian cancer (Serova-Sinilnikova OM et al. Am. J. Hum. Genet. 1997 May; 60(5):1236-9). 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	RCV000486394	SCV000889088	pathogenic	not provided	2018-02-22	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031607	SCV001434854	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-10-08	criteria provided, single submitter	clinical testing	The c.6206T>G (p.Leu2069*) variant in the BRCA2 gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA decay. This variant is absent from large databases of genetic variation in the general population. This variant has been reported in one patient with breast cancer (PMID 16912212). Another variant in the BRCA2 gene, c.6206delT, predicting to result in the same p.Leu2069* amino acid change, has been reported in a family affected with breast and ovarian cancer (PMID 9150172). Therefore, the c.6206T>G (p.Leu2069*) variant in the BRCA2 gene is classified as pathogenic.
Sema4, Sema4	RCV000568590	SCV002536209	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-22	criteria provided, single submitter	curation
Baylor Genetics	RCV003473198	SCV004212837	pathogenic	Familial cancer of breast	2022-02-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031607	SCV004839081	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-08	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 an individual affected with breast cancer (PMID: 16912212), one unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_004908) and in four families among the CIMBA participants (PMID: 29446198). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044867	SCV004848053	pathogenic	Hereditary breast ovarian cancer syndrome	2019-01-17	criteria provided, single submitter	clinical testing	The p.Leu2069X variant in BRCA2 has been reported in at least 3 individuals with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database and Sharing Clinical Reports Project). It was also absent from large population studies. This nonsense variant leads to a premature termination codon at position 2069, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300999). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting.
Sharing Clinical Reports Project (SCRP)	RCV000031607	SCV000054214	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031607	SCV000146789	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044867	SCV000587831	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000486394	SCV001554128	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Leu2069* variant was identified in a multicenter (consortia) study by CIMBA in 2 of 22702 proband chromosomes (frequency: 0.00009) from females with BRCA2 pathogenic variants, the affected individuals being Caucasian American (Rebbeck 2018). The variant was also identified in dbSNP (ID: rs80358859) as “With Pathogenic allele”, in ClinVar (classified pathogenic, reviewed by an expert panel (2016); submitters: GeneDx, Invitae, Ambry Genetics, ENIGMA, CIMBA, and 3 other laboratories), and LOVD 3.0 (1x as pathogenic). The variant was not identified in the UMD-LSDB database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.6206T>G variant leads to a premature stop codon at position 2069 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.