ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1392C>T (p.Thr464=) (rs533802049)

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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) RCV000495607 SCV000577996 benign Breast-ovarian cancer, familial 1 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; and frequency 0.001 (East Asian), derived from ExAC (2014-12-17).
GeneDx RCV000123893 SCV000167240 benign not specified 2014-05-21 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.
Ambry Genetics RCV000163142 SCV000213659 likely benign Hereditary cancer-predisposing syndrome 2014-08-05 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV001081938 SCV000259709 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240797 SCV000265883 uncertain significance Breast neoplasm 2015-11-01 criteria provided, single submitter research
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000123893 SCV000586879 likely benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163142 SCV000682955 likely benign Hereditary cancer-predisposing syndrome 2015-12-28 criteria provided, single submitter clinical testing
Counsyl RCV000495607 SCV000785171 likely benign Breast-ovarian cancer, familial 1 2017-05-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758786 SCV000887621 likely benign not provided 2018-06-26 criteria provided, single submitter clinical testing
Mendelics RCV000495607 SCV001140606 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000123893 SCV001362758 benign not specified 2019-04-10 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1392C>T results in a synonymous change. 5/5 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 0.00011 in 301874 control chromosomes, predominantly at a frequency of 0.0016 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1392C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, predominantly of Chinese ethnicity (Bhaskaran_2019, Judkins_2005, Sun_2014, Tang_1999, Zhong_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions from clinical diagnostic laboratories and an expert panel cite the variant predominantly as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000758786 SCV001501181 likely benign not provided 2020-10-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355160 SCV001549955 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Thr464= variant was identified in 9 of 111520 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer (Judkins 2005, Tang 1999). The variant was also identified in dbSNP (ID: rs533802049) as With other allele, ClinVar (classified as benign by Enigma, GeneDx; classified as likely benign by Ambry Genetics, Invitae), Clinvitae (conflicting interpretations of pathogenicity by ClinVar; likely benign by Invitae), Genesight-COGR (benign, likely benign, uncertain significance), UMD-LSDB (1X as class3), Zhejiang Colon Cancer Database (1X), databases. The variant was not identified in LOVD 3.0, BIC Database, ARUP Laboratories, databases. The variant was identified in control databases in 31 of 276894 chromosomes at a frequency of 0.000112 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include EastAsian in 31 of 18866 chromosomes (freq: 0.0016), while the variant was not observed in the African, Other, Latino, EuropeanNon-Finnish, AshkenaziJewish, EuropeanFinnish, and SouthAsian populations. The p.Thr464= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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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