Submissions for variant NM_007294.4(BRCA1):c.671-12del

dbSNP: rs273902781

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000482495	SCV000494434	benign	not specified	2019-04-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.671-12delG alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00036 in 217658 control chromosomes, predominantly at a frequency of 0.0027 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant, c.671-12delG, has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Saxena_2006, DArgenio_2015, Trujillano_2014). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x benign, 4x likely benign). Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV001086518	SCV000560305	benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000679703	SCV000564718	likely benign	not provided	2020-09-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17018160, 31131967)
Color Diagnostics, LLC DBA Color Health	RCV000579630	SCV000683344	likely benign	Hereditary cancer-predisposing syndrome	2015-09-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679703	SCV000806981	likely benign	not provided	2017-07-06	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001086518	SCV002026012	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000579630	SCV002537886	likely benign	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000482495	SCV004242846	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083076	SCV000115150	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2009-02-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083076	SCV000145654	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353643	SCV000591294	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 c.671-12delG variant was identified in 4 of 408 proband chromosomes (frequency: 0.010) from individuals or families with hereditary breast and ovarian cancer in the Northern Indian population, and was not identified in 280 control chromosomes from healthy individuals (Saxena 2006). The variant was also identified in ClinVar database (as “uncertain significance” by BIC and “benign” by SCRP) and the Exome Aggregation Consortium database (August 8, 2016) in 1 of 64096 chromosomes (freq. 1.56x10-5) in the following populations: European (Non-Finish) in 1 of 33020 chromosomes (freq. 3.03x10-5) but was not seen in African, East Asian, East African, Finish, Latio, South Asian or other populations. The variant was not found in dbSNP, Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, ARUP Laboratories BRCA Mutations Database, COSMIC, GeneInsight COGR database, and UMD. The c.671-12delG variant is located in the 3' splice 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 addition, all in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicted no alteration in splicing. The variant was identified in one individuals from our lab as co-occurring with a pathogenic BRCA2 variant (c.8754+1G>A), increasing the likelihood that the c.671-12delG variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000679703	SCV001906258	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000679703	SCV001972362	likely benign	not provided		no assertion criteria provided	clinical testing