Submissions for variant NM_007294.4(BRCA1):c.5074+1G>T

dbSNP: rs80358053

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031211	SCV001161633	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 = 0.998992
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031211	SCV000326133	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000482341	SCV000568399	pathogenic	not provided	2016-08-02	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5074+1G>T or IVS16+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 16 of the BRCA1 gene. Using alternate nomenclature, this variant has previously been published as BRCA1 5193+1G>T and IVS17+1G>T. This 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 has been reported in multiple individuals with a personal and/or family history consistent with Hereditary Breast and Ovarian Cancer (Choi 2004, Kang 2015, Gonzalez-Rivera 2016, Seifert 2016). Brose et al. (2004) performed RT-PCR studies that revealed that this variant produces a truncated protein product. In addition, Steffensen et. al. (2014) used a mingene assay to further evaluate the splicing defect caused by this variant and two aberrant transcripts were observed, both of which are expected to result in a truncated protein product. Based on the current evidence, we consider this variant to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000772123	SCV000905198	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-04	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +1 position of intron 16 of the BRCA1 gene. This variant is also known as 5193+1G>T and IVS17+1G>T based on Breast Cancer Information Core (BIC) nomenclature. Functional RNA studies have shown that this variant leads to the activation of a cryptic splice site and results in the premature truncation of the BRCA1 protein (PMID: 15345110, 24667779). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals affected with early onset breast cancer and ovarian cancer (PMID: 15117986, 22711857, 22752604, 30078507, 34657357), and has been identified in six families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496776	SCV001585897	pathogenic	Hereditary breast ovarian cancer syndrome	2024-02-20	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 16 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 breast and/or ovarian cancer (PMID: 15117986, 22752604, 29446198, 30078507, 30350268). This variant is also known as IVS17+1G>T. ClinVar contains an entry for this variant (Variation ID: 37630). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 15345110, 24667779; Invitae). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496776	SCV001983628	pathogenic	Hereditary breast ovarian cancer syndrome	2021-09-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5074+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: Three predict the variant abolishes a 5' splicing donor site. Three predict the variant abolishes a 3' acceptor site. In a functional study, this variant was reported to lead to inclusion of intronic sequence resulting in early termination of the BRCA1 protein (Brose_2004). The variant was absent in 251352 control chromosomes. c.5074+1G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Juwle_2012, Li_2018, Ryu_2019, Cecener_2020, etc). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000772123	SCV002644104	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-17	criteria provided, single submitter	clinical testing	The c.5074+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 15 of the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. This variant has been identified in multiple studies of BRCA1/2 mutation positive families (Rashid MU et al. Hered Cancer Clin Pract, 2019 Sep;17:27; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620) and has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Nones K et al. Ann. Oncol., 2019 07;30:1071-1079; Laitman Y et al. Hum. Mutat., 2019 11;40:e1-e23; Kim HN et al. Chonnam Med J, 2019 May;55:99-103; Li A et al. Gynecol. Oncol., 2018 10;151:145-152; Darooei M et al. Tumour Biol., 2017 Feb;39:1010428317694303; Juwle A et al. Med. Oncol., 2012 Dec;29:3272-81; Choi DH et al. J. Clin. Oncol., 2004 May;22:1638-45). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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). 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Sharing Clinical Reports Project (SCRP)	RCV000031211	SCV000053811	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2007-03-20	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031211	SCV000145289	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-04-12	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496776	SCV000587451	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000031211	SCV001237535	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro