Submissions for variant NM_007294.4(BRCA1):c.5193+1G>T

dbSNP: rs80358004

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160001	SCV000210206	pathogenic	not provided	2018-12-05	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA1 c.5193+1G>T or IVS18+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 18 of the BRCA1 gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant, also defined as 5312+1G>T or IVS19+1G>T using alternate nomenclature or exon numbering, has been reported in at least two individuals with breast cancer and one with ovarian cancer (Spurdle 2008, Seifert 2016). In a functional study, this variant was classified as non-functional based on a saturation genome editing (SGE) assay measuring growth in a BRCA1 null cell line (Findlay 2018). Based on current evidence, we consider this variant to be pathogenic.
Invitae	RCV000496615	SCV000940677	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 18 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted 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 ovarian cancer and peritoneal cancer (PMID: 26681312, 27083775). ClinVar contains an entry for this variant (Variation ID: 91642). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects BRCA1 function (PMID: 30209399). Studies have shown that disruption of this splice site results in skipping of exon 18 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001023694	SCV001185607	pathogenic	Hereditary cancer-predisposing syndrome	2019-09-26	criteria provided, single submitter	clinical testing	The c.5193+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 17 of the BRCA1 gene. 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. In silico splice site analysis predicts that this alteration will weaken the native splice donor site, however, direct evidence is insufficient at this time (Ambry internal data). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496615	SCV002819489	pathogenic	Hereditary breast ovarian cancer syndrome	2022-12-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5193+1G>T 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. The variant was absent in 251130 control chromosomes. c.5193+1G>T has been reported in the literature in individuals affected with Breast Cancer, Ovarian Cancer, and Peritoneal Cancer (Carter_2018, Ren_2021, Seifert_2016, Susswein_2016). These data indicate that the variant is likely to be associated with disease. At least one functional study reports experimental evidence evaluating an impact on protein function and showed a loss of function effect of this variant on homology directed repair (HDR) activity (Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Three laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000160001	SCV002822393	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PM2, PS3:Supporting
Baylor Genetics	RCV000077159	SCV004216943	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-07-01	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077159	SCV000108956	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-05-18	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496615	SCV000587476	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000077159	SCV001242335	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000160001	SCV001554191	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA1 c.5193+1G>T variant was identified in 5 of 1008 proband chromosomes (frequency: 0.005) from individuals or families with breast and ovarian cancer and was not identified in 460 control chromosomes from healthy individuals (Greenman, 1998, Spurdle, 2008, Seifert, 2016). The variant was also identified in dbSNP (ID: rs80358004) as "With Pathogenic allele", ClinVar (3x as Pathogenic by GeneDx, Sharing Clinical Reports Project and one other submitter). The variant was classified as a pathogenic variant by the Sharing Clinical Reports Project (SCRP) (derived from Myriad reports). The variant was not identified in LOVD 3.0, UMD-LSD. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.5193+1G>T variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. RNA studies and sequencing of the cDNA from a patient revealed skipping of exon 18, which introduces a frameshift and termination at codon 1719 (Greenman, 1998). In a functional study, this variant was classified as non-functional based on a saturation genome editing (SGE) assay measuring growth in a BRCA1 null cell line (Findlay 2018). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.