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

gnomAD frequency: 0.00001  dbSNP: rs80358086

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000048724	SCV000076737	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-05	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 disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast and ovarian cancer (PMID: 10406662, 21120943, 21324516, 21965345, 24729269). This variant is also known as IVS16+6T>C. ClinVar contains an entry for this variant (Variation ID: 37620). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice donor site and introduces a premature termination codon (PMID: 10406662, 22505045). The resulting mRNA is expected to undergo nonsense-mediated decay. 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: 11179017, 16619214, 22160602). 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.
Ambry Genetics	RCV000131837	SCV000186892	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-14	criteria provided, single submitter	clinical testing	The c.4986+6T>C pathogenic mutation results from a T to C substitution 6 nucleotides after coding exon 14 in the BRCA1 gene. This alteration has been identified in multiple patients with early-onset breast cancer (Pal T et al. Cancer. 2015 Dec;121(23):4173-80; Biunno I et al. Fam. Cancer 2014 Sep;13(3):437-44; Rummel SK et al. Breast Cancer Res. Treat. 2017 Aug;164(3):593-601), as well as in ovarian cancer cohorts (Akbari MR et al. J. Med. Genet. 2011 Nov;48(11):783-6; Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7). RNA splicing assays have shown that this mutation activates a cryptic splice donor site, resulting in an insertion, frameshift, and premature truncation (Scholl T et al. Am. J. Med. Genet. 1999; 85:113-6; Houdayer C. Hum. Mutat.. 2012 Aug; 33(8):1228-38; Ambry internal data). In addition, one 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). Of note, this alteration is also designated as IVS16+6T>C in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as a pathogenic mutation.
GeneDx	RCV000159997	SCV000210190	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in aberrant splicing and a truncated protein (Scholl 1999, Uchikawa 2007); Observed in multiple individuals with personal and/or family histories consistent with Hereditary Breast and Ovarian Cancer (Scholl 1999, Akbari 2011, Lynce 2015, Pal 2015, Rummel 2017); Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as 5105+6T>C and IVS16+6T>C; This variant is associated with the following publications: (PMID: 26913838, 21965345, 21324516, 23348723, 22505045, 10406662, 24729269, 23239986, 26250392, 26287763, 25782689, 23192404, 28727877, 28087643, 28503720, 30209399, 31159747, 33646313, 30787465, 17851636)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735559	SCV000219254	pathogenic	Breast and/or ovarian cancer	2017-03-03	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031201	SCV000326085	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000159997	SCV000484492	likely pathogenic	not provided	2015-07-24	criteria provided, single submitter	clinical testing
Counsyl	RCV000031201	SCV000677655	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131837	SCV000683231	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-01	criteria provided, single submitter	clinical testing	This variant causes a T>C nucleotide substitution at the +6 position of intron 15 of the BRCA1 gene. This variant is also known as IVS16+6T>C in the literature. RNA studies on carrier-derived RNA have found this variant to disrupt splicing in a manner that is expected to result in an absent or non-functional protein product (PMID: 10406662, 22505045). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in multiple individuals with personal and/or family history of breast and ovarian cancer (PMID: 10406662, 18703817, 21120943, 21324516, 24729269, 28503720). 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.
GeneKor MSA	RCV000159997	SCV000693498	likely pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change occurs 6 nucleotides after exon 16 of the BRCA1 gene. This position is conserved in the human genome and is crucial in mRNA processing. This mutation is expected to result in incorrect splicing, alteration in the reading frame and an absent or truncated protein. This variant is also known as IVS16+6T>C and has been reported in the international literature in patients with hereditary breast and ovarian cancer (PMID: 21324516, 21965345, 21120943). Experimental studies have shown that this sequence change creates an aberrant transcript by activating a cryptic splice donor site. Moreover, this prediction has been confirmed experimentally (PMID: 10406662, 22505045). The mutation database Clinvar contains entries for this variant (Variation ID:37620) In summary, this is a rare sequence change that is expected to affect the BRCA1 protein and cause disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048724	SCV000699190	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4986+6T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. One predict the variant weakens the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by using a cryptic site 65 nucleotides downstream of the canonical 5' splice donor site (Houdayer_2012). The variant was absent in 249776 control chromosomes. c.4986+6T>C has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Findlay_2018). The most pronounced variant effect results in loss of HDR activity. Multiple 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031201	SCV000744604	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV000031201	SCV001424820	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-04-01	criteria provided, single submitter	clinical testing	The c.5049+6T>C variant (also known as IVS16+6T>C) affects a cryptic splice donor site and leads to an aberrant transcript and truncated protein (Scholl 1999, Houdayer 2012). A different sequence change at the same position has also been shown to result in abnormal splicing (Chen 2006). The c.5049+6T>C variant has been reported in multiple individuals and families with breast and ovarian cancer (Scholl 1999, Zhang 2011, Akbari 2011, Caux-Moncoutier 2011, Biunno 2014). Thus, the c.5049+6T>C variant is interpreted as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000031201	SCV002512514	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-01-05	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 moderate, PM2 moderate, PP1 supporting, PP3 supporting
Sema4, Sema4	RCV000131837	SCV002537799	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	curation
Baylor Genetics	RCV000031201	SCV004215087	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-23	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031201	SCV000053801	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-02-09	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031201	SCV000145238	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	RCV000048724	SCV000587440	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031201	SCV000733602	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735559	SCV000863697	likely pathogenic	Breast and/or ovarian cancer	2015-05-06	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031201	SCV001243880	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000159997	SCV001906304	pathogenic	not provided		no assertion criteria provided	clinical testing