ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1616C>T (p.Thr539Met)

gnomAD frequency: 0.00003  dbSNP: rs80357374
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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) RCV000111655 SCV001161488 benign Breast-ovarian cancer, familial, susceptibility to, 1 2019-06-18 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 = 0.000273
Invitae RCV000225759 SCV000075555 benign Hereditary breast ovarian cancer syndrome 2021-12-16 criteria provided, single submitter clinical testing
GeneDx RCV000586975 SCV000209930 likely benign not provided 2019-12-12 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 12491499, 24728327, 15235020, 26535628, 25801821, 20167696, 27616075, 29297111, 30287823, 31131967, 31825140, 33087888)
Ambry Genetics RCV000162708 SCV000213169 likely benign Hereditary cancer-predisposing syndrome 2019-02-01 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Other strong data supporting benign classification
Counsyl RCV000111655 SCV000488835 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2016-06-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586975 SCV000600259 likely benign not provided 2020-02-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586975 SCV000698878 benign not provided 2016-03-17 criteria provided, single submitter clinical testing Variant Summary: The variant of interest causes a misense change involving a non-conserved nucleotide with 3/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 11/120938 (1/10993), predominantly in the South Asian cohort, 9/16496 (1/1832), which does not exceed the predicted maximum expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest has been reported in multiple affected individuals via publications and databases, which indicate the variant to co-occur with pathogenic BRCA1 variants, c.1687C>T (p.Gln563X - classified as pathogenic by LCA) and c.5030_5033delCTAA (p.Thr1677IlefsX2 - classified as pathogenic by LCA) and 3 different BRCA2 variants, c.2808_2811delACAA(p.Lys936_Gln937?fs) c.6037A>T (p.Lys2013Ter) and c.3975_3978dupTGCT (p.Ala1327fsX4), indicating a benign role. In addition, multiple reputable clinical laboratories cite the variant as "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.
Color Health, Inc RCV000162708 SCV000910914 benign Hereditary cancer-predisposing syndrome 2016-11-14 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170824 SCV001333442 likely benign Breast and/or ovarian cancer 2019-05-14 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000162708 SCV002538043 likely benign Hereditary cancer-predisposing syndrome 2021-11-27 criteria provided, single submitter curation
ITMI RCV000120282 SCV000084434 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000111655 SCV000144144 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000120282 SCV002551033 benign not specified 2021-11-17 no assertion criteria provided clinical testing

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