ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.81-6T>C (rs80358179)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123287 SCV000166594 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768652 SCV000219181 uncertain significance Breast and/or ovarian cancer 2015-12-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031284 SCV000296382 uncertain significance Breast-ovarian cancer, familial 1 2016-03-16 criteria provided, single submitter clinical testing
GeneDx RCV000423870 SCV000512276 benign not specified 2015-03-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000123287 SCV000586862 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000581130 SCV000683366 likely benign Hereditary cancer-predisposing syndrome 2015-03-11 criteria provided, single submitter clinical testing
Counsyl RCV000031284 SCV000785548 uncertain significance Breast-ovarian cancer, familial 1 2017-09-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000423870 SCV000916763 benign not specified 2021-04-24 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.81-6T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 249574 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 0.001), allowing no conclusion about variant significance. c.81-6T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer (example, Judkins_2005, Simard_2007, Spearman_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in the BIC database (BRCA2 c.8537_8538delAG, p.Glu2846fsX22), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on Homology Directed Repair (HDR) capacity (example, Findlay_2018). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=3; likely benign, n=1; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
Sharing Clinical Reports Project (SCRP) RCV000031284 SCV000053889 benign Breast-ovarian cancer, familial 1 2009-12-23 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031284 SCV000144228 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353944 SCV000591237 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 c.81-6T>C variant was identified in 1 of 512 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer (Simard 2007). The variant was also identified in the following databases: dbSNP (ID: rs80358179) as "With other, untested allele", ClinVar (3x benign, 1x likely benign, 5x uncertain significance), Clinvitae, GeneInsight-COGR (4x, uncertain significance), LOVD 3.0 (1x), UMD-LSDB (10x, likely neutral), and the BIC Database (5x, clincial importance unknown). The variant was classified as a benign variant by the Sharing Clinical Reports Project (SCRP) (derived from Myriad reports). The variant was identified by our laboratory in five individuals with breast cancer. The variant was not identified in Cosmic, MutDB, ARUP Laboratories, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 10 of 244486 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European in 10 of 110782 chromosomes (freq: 0.00009); while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. Another substitution at this same position (c.81-6T>A) has been previously identified in a breast cancer patient, and through functional studies (analysis of cDNA transcript) has been shown to create a cryptic pathogenic splice site (Vreeswijk 2009). The c.81-6T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Brotman Baty Institute,University of Washington RCV000031284 SCV001242790 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
King Laboratory,University of Washington RCV000423870 SCV001251289 benign not specified 2019-09-01 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.