Submissions for variant NM_007294.4(BRCA1):c.3389C>G (p.Ser1130Ter)

dbSNP: rs80357405

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031109	SCV000299936	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.
GeneDx	RCV000236909	SCV000293195	pathogenic	not provided	2017-11-29	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA1 c.3389C>G at the cDNA level and p.Ser1130Ter (S1130X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 3508C>G. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least two individuals with hereditary breast and/or ovarian cancer and co-segregated with associated cancers in one of these families (Plummer 1995, Borg 2010). We consider variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031109	SCV000325643	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236909	SCV000600330	pathogenic	not provided	2017-06-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001180645	SCV001345624	pathogenic	Hereditary cancer-predisposing syndrome	2019-08-22	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. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 20104584, 30555256). 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. Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV001180645	SCV002618242	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-31	criteria provided, single submitter	clinical testing	The p.S1130* pathogenic mutation (also known as c.3389C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 3389. This changes the amino acid from a serine to a stop codon within coding exon 9. This alteration has been reported in the literature in multiple cohorts of BRCA1/2 mutation positive families (Plummer SJ, Hum. Mol. Genet. 1995 Oct; 4(10):1989-91; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620; Mehta A et al. Cancer Manag Res, 2018 Nov;10:6505-6516). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496618	SCV003443091	pathogenic	Hereditary breast ovarian cancer syndrome	2022-10-25	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: 37528). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29446198, 30555256). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1130*) 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).
Sharing Clinical Reports Project (SCRP)	RCV000031109	SCV000053705	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-11-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031109	SCV000144746	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	RCV000496618	SCV000587307	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000031109	SCV004244046	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing