Submissions for variant NM_007294.4(BRCA1):c.547+2T>A

dbSNP: rs80358047

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031255	SCV000282246	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-03	reviewed by expert panel	curation	Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.442_547del transcript (encoding predicted non-functional protein).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000034759	SCV000077022	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-10	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 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 breast and/or ovarian cancer (PMID: 9333265, 23940062, 25556971). This variant is also known as IVS8+2T>A. ClinVar contains an entry for this variant (Variation ID: 37674). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24667779). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481282	SCV000296429	pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-donor site and interferes with normal BRCA1 mRNA splicing. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 23940062 (2013), 25452441 (2015), 25556971 (2015)) and ovarian cancer (PMID: 30606148 (2019), 25556971 (2015)). Published functional studies show that this variant causes aberrant mRNA splicing that result in skipping of exon 8 (PMID: 10479726 (1999), 22505045 (2012), 23451180 (2013), 24667779 (2014)). 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	RCV000031255	SCV000326327	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000481282	SCV000568433	pathogenic	not provided	2020-08-03	criteria provided, single submitter	clinical testing	Canonical splice site variant resulting in a null allele in a gene for which loss-of-function is a known mechanism of disease (Houdayer 2012, Colombo 2013, Steffensen 2014); Observed in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Shattuck-Eidens 1997, Turner 1999, Smith 2000, Grushko 2004, Johnston 2012, Colombo 2013); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as c.666+2T>A or IVS8+2T>A; This variant is associated with the following publications: (PMID: 23940062, 9333265, 25556971, 23451180, 28423363, 27328445, 29346284, 30606148, 22703879, 26046366, 25525159, 22505045, 10479726, 24667779, 14760071, 10506595, 17284709, 11121624, 27600092, 29446198, 33287145)
Ambry Genetics	RCV000563139	SCV000665799	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-14	criteria provided, single submitter	clinical testing	The c.547+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 6 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been detected in numerous patients and families affected with breast and/or ovarian cancer (Pyne MT et al. Mutat. Res. 1999 Aug;406:101-7; Johnston JJ et al. Am. J. Hum. Genet. 2012 Jul;91:97-108; Tedaldi G et al. Oncotarget 2017 Jul;8:47064-47075; Marchetti C et al. Ann. Surg. Oncol. 2018 Nov;25(12):3701-3708; Cotrim DP et al. BMC Cancer. 2019 Jan;19(1):4). RNA studies have demonstrated that this alteration causes coding exon 6 skipping (total exon 8 in the literature), which results in a transcript that is subject to nonsense-mediated mRNA decay (Ambry internal data; Pyne MT et al. Mutat. Res. 1999 Aug;406:101-7; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Colombo M et al. PLoS ONE 2013 Feb;8:e57173). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000031255	SCV000785772	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-11-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000563139	SCV000905208	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-10	criteria provided, single submitter	clinical testing	This variant causes a T to A nucleotide substitution at the +2 position of intron 7 of the BRCA1 gene. RNA studies have reported that the variant causes the out-of-frame skipping of exon 7, resulting in premature termination, in RNA derived from carriers and in a minigene splicing assay (PMID: 10479726, 22505045, 23451180, 24667779). This variant has been detected in at least seven individuals affected with breast or ovarian cancer (PMID: 10479726, 25452441, 27328445, 28423363, 30128899, 30606148; Color internal data). This variant has not been identified 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.
Sema4, Sema4	RCV000563139	SCV002537862	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-28	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000031255	SCV002556781	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-03-01	criteria provided, single submitter	clinical testing	The BRCA1:c.547+2T>A variant is classified as PATHOGENIC (ENIGMA criteria 2017) BRCA1:c.547+2T>A is a single nucleotide substitution in intron 8 at +2 bases from the last nucleotide of exon 8. BRCA1:c.547+2T>A is also described as IVS8+2T>A in the scientific literature using legacy nomenclature. This variant is predicted to effect aberrant splicing. Functional studies confirm BRCA1:c.547+2T>A results in skipping of exon 8 generating a frameshift transcript (BRCA1:r.442_547) that encodes premature termination of the protein synthesis (BRCA1:p.Gln148AspfsTer51) (Houdayer et al., 2012, PMID:22505045, Colombo et al., 2013, PMID:23451180). This variant has been reviewed by the ENIGMA expert review panel: ENIGMA determine BRCA1:c.547+2T>A as consistent with an IARC Class 5 variant equivalent to ACMG classification of Pathogenic. BRCA1:c.547+2T>A (rs80358047) is absent from population databases and is not on record in FLOSSIES. BRCA1:c.547+2T>A has been reported in multiple unrelated individuals with breast or ovarian cancer (Marchetti et al., 2018, PMID:30128899, Shattuck-Eidens et al., 1997 PMID:9333265, Trujillano et al., 2015 PMID:25556971). BRCA1:c.547+2T>A is on record in ClinVar (Variation ID:37674) reported by multiple clinical laboratories without conflict as pathogenic in association with Hereditary breast and ovarian cancer syndrome. This variant is listed in HGMD as ‘disease causing mutation’ in association with breast and/or ovarian cancer (Accession:CS973719).
MGZ Medical Genetics Center	RCV000031255	SCV002580843	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-02-10	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149593	SCV003838251	pathogenic	Breast and/or ovarian cancer	2022-02-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031255	SCV004215133	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-11	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034759	SCV000043187	pathogenic	Hereditary breast ovarian cancer syndrome	2012-07-13	no assertion criteria provided	research	Converted during submission to Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031255	SCV000053859	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031255	SCV000145615	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000034759	SCV000587064	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research