Submissions for variant NM_007294.4(BRCA1):c.671-6T>G

dbSNP: rs878854964

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230230	SCV000289838	uncertain significance	Hereditary breast ovarian cancer syndrome	2016-02-24	criteria provided, single submitter	clinical testing	This sequence change falls in intron 9 of the BRCA1 mRNA. It does not directly change the encoded amino acid sequence of the BRCA1 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a novel intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001183555	SCV001349334	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000503426	SCV001363879	uncertain significance	not specified	2019-02-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.671-6T>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict an impact on normal splicing: Four predict the variant weakens a 3 acceptor site. One predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 254334 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.671-6T>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353506	SCV000591293	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The c.671-6T>G variant has not been previously identified in the literature. This 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-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) predicts modest impact on the splicing scores, however this observation is inadequate for assessing pathogenicity. 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 (VUS).
Center for Precision Medicine, Meizhou People's Hospital	RCV002250602	SCV002520907	uncertain significance	Familial cancer of breast		no assertion criteria provided	curation