ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.548-17G>T (rs80358014)

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Total submissions: 13
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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) RCV000031256 SCV000244403 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 = 0.000000319
GeneDx RCV000123884 SCV000167229 benign not specified 2014-02-24 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.
Invitae RCV001080593 SCV000252821 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000031256 SCV000488470 benign Breast-ovarian cancer, familial 1 2016-04-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000123884 SCV000602721 benign not specified 2017-01-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000580272 SCV000683325 benign Hereditary cancer-predisposing syndrome 2015-02-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586208 SCV000699264 benign not provided 2016-06-07 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.548-17G>T variant causing the alteration of a non-conserved intronic nucleotide with 5/5 in silico programs predicting no significant effect on splicing, which is supported by multiple functional studies. This variant was observed in the large, broad control population, ExAC, with an allele frequency of 20/119928 (1/5995, frequency: 0.0001668), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000 (0.0010005). The variant of interest has been reported in multiple affected individuals via publications with limited information (ie, lack of co-occurrence and cosegregation data). However, the variant has been reported to co-occur with other pathogenic variants, BRCA1, c.2722G>T and BRCA2 variants, c.8237_8238delCA (p.Thr2736SerfsX17), c.2930_2940del and c.1202C>A (p.Ser401X). In addition, multiple publications and reputable databases/clinical laboratories cite the variant as "Benign/Neutral." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign.
PreventionGenetics,PreventionGenetics RCV000123884 SCV000806976 benign not specified 2017-06-29 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196702 SCV001367333 benign Familial cancer of breast 2019-10-17 criteria provided, single submitter clinical testing This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BP6,BP4.
Sharing Clinical Reports Project (SCRP) RCV000031256 SCV000053860 benign Breast-ovarian cancer, familial 1 2009-04-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031256 SCV000145619 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Medical Genetics, University Hospital of North Norway RCV000031256 SCV000301428 likely benign Breast-ovarian cancer, familial 1 2016-05-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000586208 SCV000591281 likely benign not provided no assertion criteria provided clinical testing The BRCA1 c.548-17G>T variant was identified in ClinVar (Bengin. Classified as benign by ENIGMA, Prevention Genetics, Invitae, Counsyl, ARUP Laboratories, Integrated Genetics, GeneDx, Centre for Mendelian Genomics at University Medical Centre Ljubljana, SCRP. Classified as likely benign by Department of Medical Genetics at University Hospital North Norway, COGR. Classified as VUS by BIC). The variant was identified in dnSNP (rs80358014). The variant has been reporting as co-occuring with pathogenic variants (BRCA1, c.2722G>T and BRCA2 variants, c.8237_8238delCA (p.Thr2736SerfsX17), c.2930_2940del and c.1202C>A (p.Ser401X), SCV000699264.1). The variant was identified in control databases in 59 of 280930 chromosomes (0 homozygous) at a frequency of 0.0002100 and was observed at the highest frequency in the European (non-Finnish) population in 47 of 128348 chromosomes (freq: 0.0003662) (Genome Aggregation Database March 6, 2019, v2.1.1).The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on 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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