Submissions for variant NM_007294.4(BRCA1):c.4117G>T (p.Glu1373Ter)

dbSNP: rs80357259

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031150	SCV000300075	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	RCV000048449	SCV000076462	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1373*) 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 (PMID: 11179017, 17591842, 26219728). This variant is also known as 4236G>T. ClinVar contains an entry for this variant (Variation ID: 37569). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000074589	SCV000108674	pathogenic	not provided	2023-03-06	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); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Nedelcu et al., 2002; Kadouri et al., 2007; Veschi et al., 2007; Grant et al., 2015; Lolas Hamameh et al., 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4236G>T; This variant is associated with the following publications: (PMID: 11179017, 23958087, 26219728, 34290354, 31336956, 32438681, 28888541, 25479140, 25722380, 17591842, 26306726, 17233897, 11938448, 25525159, 26187060, 28152038, 27928164, 29907814, 28486781, 11773283, 23996866, 12655515, 11870168, 30606148, 29484706, 29446198, 32733560, 31589614)
Ambry Genetics	RCV000162872	SCV000213359	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-26	criteria provided, single submitter	clinical testing	The p.E1373* pathogenic mutation (also known as c.4117G>T) located in coding exon 10 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4117. This changes the amino acid from a glutamic acid to a stop codon within coding exon 10. This alteration has been identified in several individuals with hereditary breast and/or ovarian cancer (HBOC) syndrome (Risch HA et al. Am. J. Hum. Genet. 2001 Mar; 68(3):700-10. Kadouri L et al. BMC Cancer 2007; 7:14. Geisler JP et al. J. Natl. Cancer Inst. 2002 Jan; 94(1):61-7; Lolas Hamameh S et al. Int. J. Cancer. 2017 Aug;141(4):750-756; Palmero E et al. Sci Rep 2018 Jun;8(1):9188). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031150	SCV000325854	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162872	SCV000537657	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 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 over two dozen individuals affected with breast and/or ovarian cancer (PMID: 11179017, 11773283, 17233897, 17591842, 30128899, 32438681), and this variant was also found to segregate with breast, ovarian or pancreatic cancer in one family (PMID: 17233897). 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.
Counsyl	RCV000031150	SCV000677652	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074589	SCV001133576	pathogenic	not provided	2018-11-23	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048449	SCV001363929	pathogenic	Hereditary breast ovarian cancer syndrome	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4117G>T (p.Glu1373X) 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 248774 control chromosomes (gnomAD). c.4117G>T has been reported in the literature in multiple individuals with breast and/or ovarian cancer, including individuals from families affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Risch_2001, Nedelcu_2002, Kadouri_2007, Giannini_2006, Capalbo_2006, Safra_2013, Marchetti_2018, Santonocito_2020) . These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters, including an expert panel (ENIGMA) have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031150	SCV003927265	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-31	criteria provided, single submitter	clinical testing	A known pathogenic variant was detected in BRCA1 gene (c.4117G>T). This sequence change creates a premature translational stop signal (p.Glul373*) 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 (PMID: 11179017, 17591842, 26219728). This variant is also known as 4236G>T. ClinVar contains an entry for this variant (Variation ID: 37569). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000031150	SCV004216888	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-11-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031150	SCV004817709	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-03-28	criteria provided, single submitter	clinical testing	The c.4117G>T (p.Glu1373*) variant of the BRCA1 gene creates an early stop codon. It is expected to result in an absent or disrupted protein product. This variant has been reported in multiple individuals with breast and ovarian cancer (PMID: 11179017, 11773283, 11938448, 16760289, 17233897, 17591842, 26219728, 28486781, 29907814, 30128899). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore, the c.4117G>T (p.Glu1373*) variant of the BRCA1 gene is classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031150	SCV000053750	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031150	SCV000144987	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048449	SCV000587375	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353510	SCV000591492	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Glu1373X variant was identified in 5 of 2418 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer, and was not identified in 300 control chromosomes from healthy individuals (Al-Ansari 2013, Burcos 2013, Geisler 2002, Kadouri 2007, Risch 2001, Scheuer 2002). The variant was also previously identified by our laboratory in an individual with breast cancer. The variant was also identified in dbSNP (ID: rs80357259) “With pathogenic allele”, HGMD, the BIC database (9X with clinical importance), and UMD (1X as a causal variant). The variant was classified as a pathogenic variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The p.Glu1373X variant leads to a premature stop codon at position 1373, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 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.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735478	SCV000863615	pathogenic	Breast and/or ovarian cancer	2002-03-21	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004730860	SCV005339868	pathogenic	BRCA1-related disorder	2024-06-04	no assertion criteria provided	clinical testing	The BRCA1 c.4117G>T variant is predicted to result in premature protein termination (p.Glu1373*). This variant was reported in multiple individuals with breast and ovarian cancer (Risch et al 2001. PubMed ID: 11179017; Palmero EI et al 2018. PubMed ID: 29907814; Table 4. Santonocito C et al 2020. PubMed ID: 32438681; Table 2.Abdel-Razeq H et al 2022. PubMed ID: 36537080; Table 2. Marchetti C et al 2018. PubMed ID: 30128899). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37569/). Nonsense variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic.