Submissions for variant NM_007294.4(BRCA1):c.4986+6T>G

dbSNP: rs80358086

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077591	SCV001161549	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 = 0.999999
Ambry Genetics	RCV000131820	SCV000186875	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing	The c.4986+6T>G intronic pathogenic mutation variant results from a T to G substitution 6 nucleotides after coding exon 14 in the BRCA1 gene. This alteration has been reported in multiple families with hereditary breast and/or ovarian cancer (Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Schneegans SM et al. Fam. Cancer. 2012 Jun;11:181-8; Schubert S et al. Int. J. Cancer 2019 Jun;144(11):2683-2694; Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620). RNA splicing analyses have shown this alteration to result in aberrant splicing that results in the insertion of 65 nucleotides and results in nonsense-mediated mRNA decay (Ambry internal data; Chen X et al. Hum. Mutat. 2006 May;27:427-35; Steffensen AY et al. Eur. J. Hum. Genet. 2014 Dec;22:1362-8). Another 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(7726):217-222). In addition, this alteration was also classified as Pathogenic in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat. 2019 Sep;40(9):1557-1578). Of note, this alteration is also referred to as 5105+6T>G and IVS16+6T>G in the published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000236376	SCV000293234	pathogenic	not provided	2024-06-28	criteria provided, single submitter	clinical testing	RNA studies demonstrate a damaging effect: results in aberrant splicing leading to a 65bp insertion and predicted null allele (PMID: 16619214); Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (PMID: 30209399); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as 5105+6 T>G and IVS16+6 T>G; This variant is associated with the following publications: (PMID: 11179017, 22160602, 24667779, 21324516, 21913181, 23348723, 31131967, 32719484, 30426508, 34645131, 31360904, 16619214, 30209399)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077591	SCV000326086	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131820	SCV000688529	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-07	criteria provided, single submitter	clinical testing	This variant causes a T>G nucleotide substitution at the +6 position of intron 15 of the BRCA1 gene. This variant is also known as 5105+6T>G and IVS16+6T>G in the literature. RNA studies on carrier-derived RNA (PMID: 16619214) and in a mini-gene splicing assay (PMID: 24667779) have found this variant to disrupt splicing in a manner that is expected to result in an absent or non-functional protein product. 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 with personal and/or family history of breast and ovarian cancer (PMID: 11179017, 16619214, 21913181, 22160602). This variant also has been reported as pathogenic in a multifactorial analysis based in part to segregation and tumor pathology likelihood ratios of 18.9 and 1134.1, respectively (PMID: 31131967). This variant has been identified in 1/249776 chromosomes 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.
Counsyl	RCV000077591	SCV000785365	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769711	SCV000901131	pathogenic	Breast and/or ovarian cancer	2017-03-08	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000077591	SCV001434960	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-02-05	criteria provided, single submitter	clinical testing	This c.4986+6T>G variant in the BRCA1 gene has been reported in multiple individuals affected with breast cancer or ovarian cancer (PMID 11179017, 16619214, 21913181, 22160602) and is extremely rare in general population databases. An RT-PCR assay using mRNA derived from an affected individual showed 65bp insertion, which is predicted to introduce a premature translation termination codon (PMID 16619214). Therefore, the c.4986+6T>G variant in the BRCA1 gene is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496750	SCV001591918	pathogenic	Hereditary breast ovarian cancer syndrome	2025-02-03	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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs80358086, gnomAD 0.0009%). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11179017, 16619214, 21913181, 22160602). ClinVar contains an entry for this variant (Variation ID: 55344). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16619214, 24667779, 30209399; internal data). This variant disrupts the c.4986+6T nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10406662, 21120943, 21324516, 21965345, 24729269). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000236376	SCV003809845	pathogenic	not provided	2022-12-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077591	SCV004212766	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077591	SCV004830386	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-28	criteria provided, single submitter	clinical testing	This variant causes a T>G nucleotide substitution at the +6 position of intron 15 of the BRCA1 gene. This variant is also known as 5105+6T>G and IVS16+6T>G in the literature. RNA studies on carrier-derived RNA (PMID: 16619214) and in a mini-gene splicing assay (PMID: 24667779) have found this variant to disrupt splicing in a manner that is expected to result in an absent or non-functional protein product. 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 with personal and/or family history of breast and ovarian cancer (PMID: 11179017, 16619214, 21913181, 22160602). This variant also has been reported as pathogenic in a multifactorial analysis based in part to segregation and tumor pathology likelihood ratios of 18.9 and 1134.1, respectively (PMID: 31131967). This variant has been identified in 1/249776 chromosomes 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.
Sharing Clinical Reports Project (SCRP)	RCV000077591	SCV000109394	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-07-23	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077591	SCV000145239	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496750	SCV000587439	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353600	SCV000591551	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The c.4986+6T>G variant has been previously reported in the literature in 1 out of 1298 proband chromosomes, in an individual with ovarian cancer (Risch 2001). The variant has also been identified by our laboratory in one family where the variant was demonstrated to segregate with disease in 5 affected family members with breast cancer, suggesting this variant is pathogenic. In the UMD, BIC and LOVD databases, an intronic mutation at the same genomic location but with a different base alteration (IVS16+16 T>C) was described as being a deleterious mutation that creates an aberrant transcript by activating a cryptic splice donor site. It is listed in the dbSNP database (rs80358086) but no frequency information was provided and so the population frequency could not be assessed. The variant is located in the 5' splice region but does not affect the highly conserved +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 summary, based on above information, this variant is classified as pathogenic.
Brotman Baty Institute, University of Washington	RCV000077591	SCV001243881	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554289	SCV001774877	pathogenic	Breast carcinoma	2021-08-08	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077591	SCV004243964	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing