Submissions for variant NM_007294.4(BRCA1):c.4986+3G>C (rs80358023)

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000048721	SCV000076734	likely pathogenic	Hereditary breast and ovarian cancer syndrome	2020-07-08	criteria provided, single submitter	clinical testing	This sequence change falls in intron 15 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with breast and/or ovarian cancer (PMID: 29446198, 12491499, 23239986, 25971625, 18465347, 23772696, 25682074). This variant is also known as IVS16+3G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 55341). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 23239986). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV000162881	SCV000213368	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-01-17	criteria provided, single submitter	clinical testing	The c.4986+3G>C intronic variant results from a G to C substitution 3 nucleotides after coding exon 14 in the BRCA1 gene. This alteration has been detected in several breast and/or ovarian cancer families as well as in a patient with triple negative breast cancer (Adem C et al. Cancer 2003 Jan; 97(1):1-11; Thomassen M et al. Acta Oncol. 2008;47(4):772-7; Singer CF et al. Clin Genet. 2014 Jan;85(1):72-5; Wong-Brown MW et al. Breast Cancer Res Treat. 2015 Feb;150(1):71-80; Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620). RT-PCR analysis of c.4986+3G>C revealed an alternate transcript with retention of 65 intronic nucleotides, and resulting in a premature termination codon (Wappenschmidt B et al. PLoS ONE 2012; 7(12):e50800). Of note, this alteration is also designated as IVS16+3G>C in published literature. This nucleotide position is well conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native donor splice site and is predicted to weaken the efficacy of the native donor splice site by ESE finder. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Counsyl	RCV000112443	SCV000221136	pathogenic	Breast-ovarian cancer, familial 1	2015-02-13	criteria provided, single submitter	literature only
GeneDx	RCV000236214	SCV000292524	likely pathogenic	not provided	2018-02-02	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.4986+3G>C or IVS15+3G>C and consists of a G>C nucleotide substitution at the +3 position of intron 15 of the BRCA1 gene. This variant is also known as BRCA1 5105+3G>C or IVS16+3G>C using alternate nomenclature. In vitro RNA analysis demonstrated that this variant causes aberrant splicing, resulting in an out-of-frame intron inclusion predicted to result in protein truncation (Wappenschmidt 2012). This variant has been observed in multiple individuals with a personal and/or family history of breast, ovarian, and/or pancreatic cancer (Adem 2003, Thomassen 2008, Muendlein 2015, Wong-Brown 2015, Dudley 2018). BRCA1 c.4986+3G>C was not observed in large population cohorts (Lek 2016). The guanine (G) nucleotide that is altered is not conserved. Based on currently available evidence, we consider BRCA1 c.4986+3G>C to be a likely pathogenic variant.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112443	SCV000326080	pathogenic	Breast-ovarian cancer, familial 1	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236214	SCV000605896	likely pathogenic	not provided	2018-06-30	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000162881	SCV000688528	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-02-06	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000236214	SCV000693496	likely pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This variant occurs three bases after exon 15 of the BRCA1 gene. Experimental studies have shown that this variant causes aberrant splicing in vitro, resulting in an out-of-frame insertion predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (PMID: 23239986). This variant has been observed in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 23239986, 12491499). This variant is also known as BRCA1 IVS16+3G>C and 5105G>C using alternate nomenclature. The mutation database ClinVar contains several entries for this variant (Variation ID: 55341).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000236214	SCV001447643	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000112443	SCV001499668	likely pathogenic	Breast-ovarian cancer, familial 1	2020-04-02	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112443	SCV000145233	pathogenic	Breast-ovarian cancer, familial 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto	RCV000048721	SCV000587438	likely pathogenic	Hereditary breast and ovarian cancer syndrome	2015-12-17	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001353420	SCV000591552	likely pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 c.4986+3G>C variant was identified in 3 of 1748 proband chromosomes (frequency: 0.002) from individuals or families with breast and ovarian cancer (Muendlein 2015, Wong-Brown 2015). The variant was also identified in dbSNP (ID: rs80358023) as “With Pathogenic allele”, Clinvitae database (as uncertain significance by ClinVar and Invitae, as Pathogenic by ClinVar), ARUP Laboratories BRCA Mutations Database (as definitely pathogenic), the ClinVar database (as uncertain significance by Invitae, Ambry Genetics; as likely pathogenic by GeneDx; as pathogenic by Counsyl and BIC), the BIC database (11X with clinical importance).rnThe c.4986+3G>C variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In addition, the variant was found in triple-negative patient in preclinical study by Wong-Brown (2015). The study suggests the variant leads to intronic retention of 65 bp and creates premature stop codon at position 1663 (p.Met1663ValfsX14) and classified it as likely pathogenic. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
Brotman Baty Institute,University of Washington	RCV000112443	SCV001243312	not provided	Breast-ovarian cancer, familial 1		no assertion provided	in vitro
King Laboratory,University of Washington	RCV001171416	SCV001251321	pathogenic	Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome	2019-09-01	no assertion criteria provided	research