ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.21C>T (p.Arg7=) (rs149402012)

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Total submissions: 15
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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) RCV000169370 SCV000577993 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 0.0053 (African), derived from ExAC (2014-12-17).
GeneDx RCV000168476 SCV000167223 benign not specified 2014-01-15 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000168476 SCV000202278 benign not specified 2014-12-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163211 SCV000213734 likely benign Hereditary cancer-predisposing syndrome 2014-09-09 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768582 SCV000219179 benign Breast and/or ovarian cancer 2017-01-18 criteria provided, single submitter clinical testing
Counsyl RCV000169370 SCV000220746 likely benign Breast-ovarian cancer, familial 1 2014-09-26 criteria provided, single submitter literature only
Invitae RCV001079978 SCV000252813 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Baylor Genetics RCV000458876 SCV000540977 benign Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000168476 SCV000593665 likely benign not specified 2016-11-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163211 SCV000683019 benign Hereditary cancer-predisposing syndrome 2015-12-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282917 SCV000885078 benign none provided 2020-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000169370 SCV001287538 likely benign Breast-ovarian cancer, familial 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Mayo Clinic Laboratories, Mayo Clinic RCV000656648 SCV000778782 likely benign not provided 2017-11-16 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000169370 SCV001237690 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357572 SCV001553078 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1, p.Arg7Arg variant was identified in 25 of 112686 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer (Fackenthal 2011, Houdayer 2012, Judkins 2005). The variant was also identified in dbSNP (ID: rs149402012) as “other”, Clinvitae database (uncertain significance by EmvClass, likely benign by ClinVar, benign by Invitae), ARUP COSMIC, the ClinVar database (uncertain significance by COG-CHEO, likely benign by Ambry Genetics and Counsyl, benign by GeneDx, Emory Genetics and Invitae), GeneInsight COGR database (uncertain significance by COG-CHEO, likely benign by COG-NYG, benign by LMM), UMD (56X with a “likely neutral” classification). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.4484G>T, p.Arg1495Met), increasing the likelihood that the p.Arg7Arg variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 8 of 5000 chromosomes (frequency: 0.002), NHLBI GO Exome Sequencing Project in 22 of 4404 African American alleles, Exome Aggregation Consortium database (August 8, 2016) in 63 (1 homozygous) of 120800 chromosomes (freq. 0.0005) in the following populations: African in 59 of 10322 chromosomes (freq. 0.006), and Latino in 4 of 11516 chromosomes (freq. 0.0003), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Arg7Arg 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, 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.

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