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

dbSNP: rs80358042

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031027	SCV001161541	pathogenic	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 5 based on posterior probability = 0.999995
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000505828	SCV000296355	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	The BRCA1 c.212+1G>A variant disrupts a canonical splice-donor site and interferes with normal BRCA1 mRNA splicing. This variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 31454914 (2019), 28294317 (2017), 23479189 (2013), 22505045 (2012), 8533757 (1995)). The frequency of this variant in the general population, 0.000004 (1/249638 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031027	SCV000325239	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031027	SCV000487791	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509688	SCV000607763	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-19	criteria provided, single submitter	clinical testing	The c.212+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the BRCA1 gene. This mutation has been reported in multiple breast and/or ovarian cancer families (Friedman LS et al. Am J Hum Genet. 1995 Dec;57(6):1284-97; de Juan Jiménez I et al. Fam Cancer. 2013 Dec;12(4):767-77; Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Several studies have shown that this alteration leads to the deletion of the last 22 base pairs of coding exon 3 and creates a premature termination codon (Ambry internal data; Friedman LS et al. Am J Hum Genet. 1995 Dec;57(6):1284-97; Menéndez M et al. Breast Cancer Res Treat. 2012 Apr;132(3):979-92; Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38; Sanz DJ et al. Clin. Cancer Res., 2010 Mar;16:1957-67). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). A multifactorial likelihood ratio analysis, which included segregation, pathology, co-occurrence, and family history data, determined that this alteration is pathogenic (Parsons MT et al. Hum. Mutat. 2019 09;40(9):1557-1578). Of note, this mutation is also designated as IVS5+1G>A in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000509688	SCV000683014	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-23	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 4 of the BRCA1 gene. RNA studies showed this variant resulted in the use of a cryptic splice donor site in exon 4 creating a premature translation termination signal and the in-frame skipping of exon 4 impacting the RING domain (PMID: 8533757, 20215541, 31843900). A functional study reported that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been detected in multiple individuals and families affected with breast and ovarian cancer (PMID: 8533757, 20215541, 22798144, 23479189, 28294317), and has been found to segregate with disease in families with a segregation likelihood ratio for pathogenicity of 1794.1757 (PMID: 8533757, 31131967). This variant has been identified in 1/249638 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496861	SCV000918781	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.212+1G>A 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: Five predict the variant abolishes a 5 splicing donor site. A functional study, Houdayer_2012, confirmed these predictions. The variant allele was found at a frequency of 4e-06 in 249638 control chromosomes (gnomAD). c.212+1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Diez_2003, Lang_2017, Kim_2012, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submissions (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496861	SCV001586071	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-22	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 present in population databases (rs80358042, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8533757, 20215541, 23479189, 28477318). ClinVar contains an entry for this variant (Variation ID: 37446). 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.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000496861	SCV002026036	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000505828	SCV002765904	pathogenic	not provided	2022-12-12	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in aberrant splicing in a gene for which loss of function is known mechanism of disease (Sanz et al., 2010, Houdayer et al., 2012; Menendez et al., 2012); Observed in individuals with BRCA1-related cancers (Esteban Cardenosa et al., 2010; Menendez et al., 2012; Wappenschmidt et al., 2012; de Juan Jimenez et al., 2013; Gabaldo Barrios et al., 2017); Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 331+1G>A and IVS5+1G>A; This variant is associated with the following publications: (PMID: 12955716, 25863477, 29088781, 28985766, 22505045, 23348723, 25525159, 16758124, 27836010, 28477318, 26071757, 28205045, 21735045, 27886673, 23479189, 25085752, 18279628, 20033483, 26026974, 26483394, 23233716, 22798144, 25236687, 23239986, 28918466, 31131967, 29922827, 30702160, 29446198, 30720243, 32341426, 31825140, 34413315, 28888541, 20104584, 24389207, 30209399, 8533757, 20215541)
Baylor Genetics	RCV000031027	SCV004212717	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-16	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031027	SCV000053621	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-10-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031027	SCV000144660	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031027	SCV000144661	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1997-09-04	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496861	SCV000587033	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735528	SCV000863666	pathogenic	Breast and/or ovarian cancer		no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031027	SCV001242562	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
King Laboratory, University of Washington	RCV001171413	SCV001251318	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1; Hereditary breast ovarian cancer syndrome	2019-09-01	no assertion criteria provided	research