Submissions for variant NM_007294.4(BRCA1):c.-19-3A>G

gnomAD frequency: 0.00004  dbSNP: rs273898669

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)	RCV000111498	SCV001161492	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000864
Counsyl	RCV000111498	SCV000489261	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000430917	SCV000516132	benign	not specified	2015-09-01	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000867026	SCV001008210	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000111498	SCV001287539	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Fulgent Genetics, Fulgent Genetics	RCV002477261	SCV002795262	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-03-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000111498	SCV004018682	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-23	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant been observed in trans with a known pathogenic variant in one or more individuals. Compound heterozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111498	SCV000143940	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-09-18	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353407	SCV000591228	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 c.-19-3A>G variant was not identified in the literature but was identified 2X in the BIC database as a variant of unknown clinical importance. This variant is located in the 3’ splice region of the BRCA1 5' untranslated region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 3 of 5 different programs, with the creation of a splice acceptor site 2 nucleotides upstream from the known splice acceptor site. The c.-19-3A>G variant is located in a region that may be involved in promoter or splicing activity, thus this variant may affect the binding of transcription factors and processing or expression of the BRCA1 mRNA transcript; however there is no supporting data for this claim. In summary, the clinical significance of this variant cannot be determined with certainty at this time. Therefore this variant is a variant of unknown significance.
Brotman Baty Institute, University of Washington	RCV000111498	SCV001242112	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
PreventionGenetics, part of Exact Sciences	RCV004758640	SCV005357636	likely benign	BRCA1-related disorder	2024-08-30	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).