ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs80358086
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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp 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 2024-03-29 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000031201 SCV005399610 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-07-17 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Fanconi anaemia, complementation group S (MIM#617883), susceptibility to breast and ovarian cancer (MIM#604370) and susceptibility to pancreatic cancer (MIM#614320). (I) 0108 - This gene is associated with both recessive and dominant disease. Susceptibility to breast and ovarian cancer follows an autosomal dominant inheritance pattern, while Fanconi anaemia is inherited in an autosomal recessive pattern (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. The highest estimate for cancer risk in carriers of pathogenic variants is 80% by the age of 70 years (PMID: 30551077). (I) 0251 - This variant is heterozygous. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Using semi-nested RT-PCR performed on total RNA isolated from patient peripheral blood cells, this variant was shown to result in a retention of a 69bp sequence in intron 15 which harbours at least one predicted STOP codon (PMID: 10406662). A subsequent study using a saturating genome editing assay demonstrated that this variant resulted in reduced mRNA expression and was functionally classified as a loss of function variant (PMID: 30209399). (SP) 0304 - Variant is present in gnomAD (v3) <0.01 for a condition (1 heterozygote, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same non-canonical splice site is present in gnomAD (v2) at a frequency of 0.0000089 (1 heterozygote, 0 homozygotes). 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another non-canonical splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The c.4986+6T>G non-canonical splice variant has been classified as 3 stars by an expert panel; however, it should be noted that the c.4986+6T>A non-canonical splice variant has been classified once as a VUS (ClinVar). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic or pathogenic by multiple clinical diagnostic laboratories (ClinVar) and has been reported in multiple individuals across different ethnicities (PMID: 29446198). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159997 SCV005626124 pathogenic not provided 2024-06-21 criteria provided, single submitter clinical testing The BRCA1 c.4986+6T>C variant has been reported in the published literature in individuals and families with breast/ovarian cancer (PMIDs: 21120943 (2011), 21324516 (2011), 21965345 (2011), 24729269 (2014), 28503720 (2017), and 33646313 (2021)). In addition, RNA studies indicated that this variant activates a cryptic splice site and causes an inclusion of extra intronic sequences which encoded a truncated BRCA1 protein (PMIDs: 10406662 (1999), 22505045 (2012), and 23239986 (2012)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA1 mRNA splicing. Based on the available information, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005016311 SCV005647124 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S 2024-04-21 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

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