Submissions for variant NM_007294.4(BRCA1):c.5152+1G>T

dbSNP: rs80358094

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112516	SCV000244415	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	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 = 1
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048820	SCV000076833	pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 17, but is expected to preserve the integrity of the reading-frame (PMID: 30209399). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 21990134). ClinVar contains an entry for this variant (Variation ID: 55423). This variant is also known as 5271+1G>T and IVS18+1G>T. Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 7493024, 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 17 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112516	SCV000326174	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771916	SCV000904693	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-09	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +1 position of intron 17 of the BRCA1 gene. This variant is also known as IVS18+1G>T in the literature. RNA study on carrier RNA has reported that this variant resulted in the skipping of exon 17 that partially encodes the BRCT domain (PMID: 30101128), and this variant also is reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in at least nine families at-risk for hereditary breast and ovarian cancer (PMID: 7493024, 29446198) and additional individuals who underwent cancer genetic testing (PMID: 18375895). Multifactorial analyses have found this variant to be deleterious with posterior probability of 1.0, based in part on likelihood ratio (deleterious) of 7562 from tumor histopathology (PMID: 18375895, 21990134). 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.
GeneDx	RCV002281895	SCV002571677	pathogenic	not provided	2022-09-12	criteria provided, single submitter	clinical testing	Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor et al., 2012); Observed in individuals with personal and/or family history of BRCA1-related cancers (Gayther et al., 1995; Spurdle et al., 2008; Kim et al., 2012; Brovkina et al., 2018; Nones et al., 2019; Frugtniet et al., 2022); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5271+1G>T and IVS18+1G>T; This variant is associated with the following publications: (PMID: 18375895, 8807330, 25525159, 22798144, 7493024, 9699523, 15345110, 30209399, 33087929, 34657373, 21990134, 30333958, 29446198, 31090900)
Ambry Genetics	RCV000771916	SCV002641329	pathogenic	Hereditary cancer-predisposing syndrome	2018-01-30	criteria provided, single submitter	clinical testing	The c.5152+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 16 of the BRCA1 gene. This intronic mutation, sometimes referred to as IVS18+1G>T and 5271+1G>T in literature, has been reported in a family with multiple members diagnosed with breast cancer before the age of 60 (Gayther SA et al. Nat. Genet. 1995 Dec;11(4):428-33). Additionally, this alteration has been classified as pathogenic by multifactorial analysis, which integrates in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results to determine a likelihood ratio of pathogenicity (Lindor NM et al. Hum. Mutat. 2012 Jan;33(1):8-21). 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). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. As such, this alteration is classified as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048820	SCV004847907	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The c.5152+1G>T variant in BRCA1 has been reported in at least 11 probands hereditary breast and/or ovarian cancer (HBOC; Gayther 1995, Brovkina 2018, BIC database). It was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant HBOC. In vitro functional studies support an impact on protein function (Findlay 2018). This variant was classified as Pathogenic on Oct 18, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 55423). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS3_Moderate, PS4_Moderate.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112516	SCV000145338	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112516	SCV001241771	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
BRCAlab, Lund University	RCV000112516	SCV004243944	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing