Submissions for variant NM_007294.4(BRCA1):c.212+1G>C

dbSNP: rs80358042

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112018	SCV000325240	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496773	SCV003933886	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.212+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. Multiple studies have reported experimental evidence that this variant affects mRNA splicing (examples: Wappenschmidt_2012 and Findlay_2018). The variant was absent in 249638 control chromosomes (gnomAD). c.212+1G>C has been reported in the literature in individuals affected with Hereditary Breast And/or Ovarian Cancer (examples: Rebbeck_2018 and Wappenschmidt_2012). Experimental evidence evaluating an impact on protein function through utilization of a cell-survival assay in a population of edited haploid HAP1 cells as a measure of functional HDR pathway, reported the variant with a functional score supporting loss of function (Findlay_2018). The following publications have been ascertained in the context of this evaluation (PMID: 30209399, 29446198, 23239986). One submitter (CIMBA) has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000112018	SCV004217015	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-12-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496773	SCV005836710	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 12960223, 29446198). This variant is also known as c.331+1G>C. ClinVar contains an entry for this variant (Variation ID: 54464). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20215541, 22505045; internal data). For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112018	SCV000144662	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496773	SCV000587036	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000112018	SCV001242563	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro