Submissions for variant NM_007294.4(BRCA1):c.2722G>T (p.Glu908Ter)

dbSNP: rs80356978

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077527	SCV000299819	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047943	SCV000075956	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu908*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 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 ovarian cancer and glioblastoma (PMID: 8554067, 19016756, 19949876, 25880076). This variant is also known as 2841G>T. ClinVar contains an entry for this variant (Variation ID: 54657). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000074576	SCV000108661	pathogenic	not provided	2020-08-25	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 a personal or family history consistent with pathogenic variants in this gene (Serova 1996, Sugano 2008, Boukerroucha 2015, Conroy 2017); Not observed 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 2841G>T; This variant is associated with the following publications: (PMID: 26010302, 25722380, 28152038, 22006311, 8554067, 22009639, 24055113, 25880076, 25637381, 10553024, 9150151, 19016756, 25452441, 18465347, 16615107, 20104584, 19949876, 14574155, 9465809, 16528604, 9667259, 12393792, 25504618, 24549055, 27767231, 28959512, 29907814, 29470806, 28724667, 30702160, 29446198, 28176296, 25525159, 31825140, 31742824, 11597388)
Ambry Genetics	RCV000131878	SCV000186933	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-09	criteria provided, single submitter	clinical testing	The p.E908* pathogenic mutation (also known as c.2722G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2722. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been reported in multiple breast and ovarian cancer (HBOC) syndrome kindreds to date (Serova O et al. Am. J. Hum. Genet. 1996 Jan;58:42-51; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Boukerroucha M et al. BMC Cancer. 2015 Mar;15:181; De Brakeleer S et al. Clin. Genet.. 2016 Mar;89:336-40; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074576	SCV000296333	pathogenic	not provided	2021-04-13	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals and families affected with breast/ovarian cancer (PMIDs: 12393792 (2002), 12068003 (2002), 29470806 (2018), 29907814 (2018), 32380732 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
GeneKor MSA	RCV000074576	SCV000296768	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This is a single base substitution, replacing the Glutamate at position 908 of the BRCA1 protein by a Termination codon. It is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. The mutation database ClinVar contains entries for this variant (Variation ID: 54657).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077527	SCV000325447	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077527	SCV000488226	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-01-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047943	SCV000494392	pathogenic	Hereditary breast ovarian cancer syndrome	2016-08-15	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2722G>T (p.Glu908X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. If a stable protein is made, Glu908X is predicted to eliminate the BRCT domain. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Val923fsX76, p.Asp936fsX63, etc.). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121362 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant was cited in multiple HBOC patients in the literature and was shown to co-segregate with disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131878	SCV000537660	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 of the BRCA1 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 multiple individuals affected with breast cancer, ovarian cancer and glioblastoma (PMID: 19016756, 22006311, 25880076, 26010302, 29470806, 32380732, 33471991, 35625946). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 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	RCV000047943	SCV000605746	pathogenic	Hereditary breast ovarian cancer syndrome	2016-10-04	criteria provided, single submitter	clinical testing	The p.Glu908X variant in BRCA1 has been reported in >60 individuals with BRCA1-a ssociated cancers (Serova 1996, Couch 2015, Boukerroucha 2015, Breast Cancer Inf ormation Core (BIC), Sharing Clinical Reports Project). This variant has been id entified in 1/8600 European chromosomes by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS/; dbSNP rs80356978). This nonsense variant leads to a premature termination codon at position 908, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with hereditary breast and ov arian cancer (HBOC). In addition, this variant was classified as Pathogenic on S eptember 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV0002998 19.2). In summary, this variant meets our criteria to be classified as pathogeni c for HBOC in an autosomal dominant manner.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000077527	SCV000743410	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077527	SCV000744648	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000077527	SCV000778595	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-10-24	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000763005	SCV000893450	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000077527	SCV001434970	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-02-01	criteria provided, single submitter	clinical testing	The c.2722G>T (p.Glu908*) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple individuals affected with breast or ovarian cancer (PMID 8554067, 19016756, 19949876, 22006311, 22009639, 25880076). This variant is not observed in gnomAD database. Therefore, the c.1953_1956delGAAA (p.Lys653Serfs*47) variant in the BRCA1 gene is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000074576	SCV001448152	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000074576	SCV002017862	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000074576	SCV002563415	pathogenic	not provided	2018-12-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077527	SCV004212756	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077527	SCV004815659	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-20	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 of the BRCA1 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 multiple individuals affected with breast cancer, ovarian cancer and glioblastoma (PMID: 19016756, 22006311, 25880076, 26010302, 29470806, 32380732, 33471991, 35625946). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000074576	SCV005199735	pathogenic	not provided	2023-07-05	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077527	SCV000109328	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077527	SCV000144522	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148387	SCV000190085	pathogenic	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000047943	SCV000587250	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000074576	SCV000591407	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077527	SCV000733636	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735484	SCV000863621	pathogenic	Breast and/or ovarian cancer	2001-10-01	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000074576	SCV001956036	pathogenic	not provided		no assertion criteria provided	clinical testing