Submissions for variant NM_007294.4(BRCA1):c.3257T>G (p.Leu1086Ter)

dbSNP: rs80357006

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083194	SCV000299903	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.
Invitae	RCV000048114	SCV000076127	pathogenic	Hereditary breast ovarian cancer syndrome	2023-03-24	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9663595, 11857748, 23479189, 24884479, 24916970). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54810). This variant is also known as 3376T>G. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu1086*) 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).
Ambry Genetics	RCV000131910	SCV000186965	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-15	criteria provided, single submitter	clinical testing	The p.L1086* pathogenic mutation (also known as c.3257T>G) is located in coding exon 9 of the BRCA1 gene. This alteration results from a T to G substitution at nucleotide position 3257. This changes the amino acid from a leucine to a stop codon within coding exon 9. This alteration has been identified in numerous high-risk breast/ovarian cancer families (Wagner et al. Int J Cancer. 1998 Jul 29;77(3):354-60; Llort et al. Hum Mutat. 2002 Mar;19(3):307; Peixoto A, Clin. Genet. 2015 Jul;88(1):41-8; de Juan Jiménez I et al. Fam. Cancer, 2013 Dec;12:767-77; Silva FC et al. BMC Med. Genet., 2014 May;15:55). Of note, this alteration is also known as 3376T>G in published literature. 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	RCV000083194	SCV000325589	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000414138	SCV000492452	pathogenic	Breast neoplasm		criteria provided, single submitter	research
GeneDx	RCV000657619	SCV000779362	pathogenic	not provided	2019-07-29	criteria provided, single submitter	clinical testing	Reported previously, as c.3376 T>G using alternate nomenclature, in multiple families with breast and/or ovarian cancer (Wagner et al., 1998; Llort et al., 2002; Beristain et al., 2010; de Juan Jimenez et al., 2013; Silva et al., 2014; Minucci et al., 2015); 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 in large population cohorts (Lek et al., 2016); Reported as pathogenic in a well-curated database but additional evidence is not available (Spurdle et al., 2012); This variant is associated with the following publications: (PMID: 26026974, 25525159, 26306726, 16287141, 23479189, 22460208, 21147080, 24884479, 22984553, 11857748, 24916970, 9663595, 28127413, 23469205, 16267036, 29907814, 29446198, 30736435, 31214711)
Mendelics	RCV000048114	SCV000839257	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131910	SCV000909312	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-16	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 individuals and families affected with breast and/or ovarian cancer (PMID: 9663595, 11857748, 23479189, 24884479, 24916970), and has been identified in 19 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048114	SCV000916708	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3257T>G (p.Leu1086X) 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 250570 control chromosomes. c.3257T>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). 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. 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000083194	SCV001429187	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-08-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000657619	SCV003809879	pathogenic	not provided	2022-04-20	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000083194	SCV004176538	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-02-14	criteria provided, single submitter	clinical testing	The stop-gained variant c.3257T>G (p.Leu1086Ter) in the BRCA1 gene has been reported in heterozygous state in individuals with hereditary breast/ovarian cancer (Peixoto et al., 2015; Silva et al., 2014). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (Multiple submissions). This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000083194	SCV004211761	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-04-14	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083194	SCV000115268	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-12-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083194	SCV000144691	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	RCV000048114	SCV000587293	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000657619	SCV001741879	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000657619	SCV001952287	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000083194	SCV004244058	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing