ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4097-11T>C (rs80358072)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112253 SCV000244354 benign Breast-ovarian cancer, familial 1 2015-08-10 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 1 based on posterior probability = 0.000542
Invitae RCV000123276 SCV000166583 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-25 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000112253 SCV000267709 likely benign Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855578 SCV000494378 likely benign not specified 2019-02-27 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4097-11T>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. 5/5 computational tools predict no significant impact on normal splicing. This prediction has been confirmed by a study that used mRNA extracted from patient derived lymphoblastoid cell lines (LCLs), and demonstrated that the variant caused no changes in mRNA splicing (Houdayer 2012). The variant allele was found at a frequency of 4.1e-06 in 241972 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4097-11T>C has been reported in the literature in individuals affected with Breast and Ovarian Cancer, however without evidence of causality (Borg 2010, Judkins 2005). In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be likely neutral (Easton 2007, Lindor 2012). Five 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 benign (1x) / likely benign (4x). Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV000583619 SCV000688465 likely benign Hereditary cancer-predisposing syndrome 2017-11-02 criteria provided, single submitter clinical testing
Counsyl RCV000112253 SCV000785367 likely benign Breast-ovarian cancer, familial 1 2017-07-14 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112253 SCV000144974 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357737 SCV001553297 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 c.4097-11T>C variant was identified in 2 of 114056 proband chromosomes (frequency: 0.00002) from individuals or families with breast cancer (Borg 2010, Judkins 2005). The variant was also identified in dbSNP (ID: rs80358072) as "With Likely benign allele", ClinVar (classified as benign by ENIGMA; as likely benign by Invitae and four other submitters; and as uncertain significance by BIC), and in LOVD 3.0 (3x).The variant was not identified in UMD-LSDB. The variant was identified in control databases in 1 of 236832 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 1 of 16956 chromosomes (freq: 0.00006), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, or South Asian populations. One study by demonstrated that the variant has no effect on splicing in vitro (Houdayer 2012). The c.4097-11T>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. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 benign role for this variant. This variant is classified as likely benign.

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