ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.671-12del (rs273902781)

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Total submissions: 8
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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 and ovarian cancer syndrome 2020-12-02 criteria provided, single submitter clinical testing
GeneDx RCV000482495 SCV000564718 likely benign not specified 2018-03-01 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.
Color Health, Inc RCV000579630 SCV000683344 likely benign Hereditary cancer-predisposing syndrome 2015-09-09 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679703 SCV000806981 likely benign not provided 2017-07-06 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083076 SCV000115150 benign Breast-ovarian cancer, familial 1 2009-02-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083076 SCV000145654 uncertain significance Breast-ovarian cancer, familial 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.

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