ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4644G>A (p.Thr1548=) (rs28897692)

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Total submissions: 8
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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) RCV000495099 SCV000578172 likely benign Breast-ovarian cancer, familial 1 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Ambry Genetics RCV000163459 SCV000214009 likely benign Hereditary cancer-predisposing syndrome 2014-06-02 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 RCV000206403 SCV000260383 benign Hereditary breast and ovarian cancer syndrome 2020-11-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163459 SCV000683197 benign Hereditary cancer-predisposing syndrome 2015-08-07 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000495099 SCV000743390 likely benign Breast-ovarian cancer, familial 1 2017-07-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286313 SCV001472859 likely benign none provided 2020-08-14 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000502663 SCV000591530 likely benign not provided no assertion criteria provided clinical testing The BRCA1 p.Thr1548Thr variant was identified in 3 of 2720 proband chromosomes (frequency: 0.001) from Romanian, Danish, other individuals or families with familial breast and ovarian cancers, and was not identified in 394 control chromosomes from healthy individuals (Negura 2011, Hansen 2011, Ozcelik 2012). The variant was identified co-occurring with a pathogenic BRCA1 variant (c.342_343delTC) in 2 Romanian cases from the same HBOC family, and a pathogenic BRCA2 variant (2041delA) in a Danish case, increasing the likelihood the variant is not clinically significant (Negura 2011, Hansen 2011). The variant was identified in dbSNP (ID: rs28897692) as “With Likely benign allele”, the NHLBI GO Exome Sequencing Project in 2 of 8600 European American alleles, and the Exome Aggregation Consortium database (August 8, 2016) in 5 of 121372 chromosomes (freq. 0.00004) in the European (Non-Finnish) population in 5 of 66728 chromosomes (freq. 0.00007)), but was not seen in African, East Asian, Finnish, Latino, Other, and South Asian populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in the Clinvitae database (classification likely benign), the ClinVar database (classification likely benign, submitters Ambry Genetics and Invitae), and UMD (5x with an “unclassified variant” classification). In UMD, the variant was identified with a co-occurring pathogenic BRCA1 variant (c.342_343delTC, p.Pro115X), increasing the likelihood that the p.Thr1548Thr variant does not have clinical significance. The p.Thr1548Thr 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. The variant occurs outside of the splicing consensus sequence and 1 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000495099 SCV000733608 likely benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing

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