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

gnomAD frequency: 0.00006  dbSNP: rs533802049

Total submissions: 14

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, susceptibility to, 1	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.001 (East Asian), derived from ExAC (2014-12-17).
GeneDx	RCV000758786	SCV000167240	benign	not provided	2018-12-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25337278, 27257965, 16267036, 10340909, 30702160)
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 ovarian cancer syndrome	2024-01-28	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 Diagnostics, LLC DBA Color Health	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, susceptibility to, 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, susceptibility to, 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000758786	SCV002048555	benign	not provided	2021-10-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163142	SCV002538019	likely benign	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	curation
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.