ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.547+14del (rs273902771)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000515646 SCV000219191 uncertain significance not specified 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV001080882 SCV000261141 benign Hereditary breast and ovarian cancer syndrome 2020-11-25 criteria provided, single submitter clinical testing
Color Health, Inc RCV000579808 SCV000683321 likely benign Hereditary cancer-predisposing syndrome 2015-05-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587246 SCV000699259 likely benign not provided 2016-11-18 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.547+14delG variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 3/5 splice prediction tools predict no significant impact on normal splicing and a functional study using a mini-gene system confirmed these prediction results, showing no abberant splicing (Steffensen_2014). This variant was found in 16/122164 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0012726 (11/8644). This frequency is about the same frequency as the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant was reported in individuals of Asian descent in the literature, without strong evidence for causality. UMD reports the variant in an individual who carried a second pathogenic BRCA1, supporting the benign role of the variant. In addition, one clinical diagnostic laboratories/reputable database has classified this variant as benign. Taken together, this variant is classified as likley benign, until additional evidence becomes available.
Counsyl RCV000112728 SCV000785397 likely benign Breast-ovarian cancer, familial 1 2017-07-24 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770749 SCV000902233 uncertain significance Breast and/or ovarian cancer 2017-05-18 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587246 SCV001249215 likely benign not provided 2020-05-01 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112728 SCV000145611 uncertain significance Breast-ovarian cancer, familial 1 2010-12-17 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354483 SCV001549111 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 c.547+14delG variant was identified in 3 of 796 proband chromosomes (frequency: 0.004) from Korean individuals or families with breast or ovarian cancer and was identified in 1 of 842 control chromosomes (frequency: 0.001) from healthy individuals (Choi 2015, Yoon 2016). A functional study using a minigene splicing assay found the variant had no effect on splicing and therefore was determined to be neutral (Steffensen_2014). The variant was also identified in dbSNP (ID: rs273902771) “With other allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: benign by Invitae, likely benign by Color Genomics Inc. and Laboratory Corporation of America, and uncertain significance by CHEO Genetics Diagnostic Laboratory and BIC), Clinvitae (3x), COGR (4 clinical laboratories with conflicting interpretations of pathogenicity), LOVD 3.0 (1x), and was not identified in Cosmic, MutDB, UMD-LSDB, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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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