ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4812A>G (p.Gln1604=) (rs28897693)

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Total submissions: 19
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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) RCV000112404 SCV000577999 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; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0043 (South Asian), derived from ExAC (2014-12-17).
Invitae RCV001084068 SCV000076678 benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
Counsyl RCV000112404 SCV000153995 likely benign Breast-ovarian cancer, familial 1 2014-01-02 criteria provided, single submitter literature only
GeneDx RCV000168511 SCV000167311 benign not specified 2013-10-18 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 RCV000162689 SCV000213143 likely benign Hereditary cancer-predisposing syndrome 2014-07-03 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 RCV000168511 SCV000219250 benign not specified 2017-03-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV000471716 SCV000540970 benign Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000168511 SCV000602733 benign not specified 2018-08-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162689 SCV000683217 benign Hereditary cancer-predisposing syndrome criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585287 SCV000692907 likely benign not provided 2017-08-01 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000112404 SCV000743388 likely benign Breast-ovarian cancer, familial 1 2014-12-29 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000112404 SCV000744608 benign Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000585287 SCV000806960 likely benign not provided 2017-05-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000112404 SCV001280754 uncertain significance Breast-ovarian cancer, familial 1 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170591 SCV001333179 likely benign Breast and/or ovarian cancer 2018-09-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112404 SCV000145186 uncertain significance Breast-ovarian cancer, familial 1 2011-07-08 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000168511 SCV000591539 benign not specified no assertion criteria provided clinical testing The BRCA1 p.Gln1604Gln variant was identified in 4 of 2576 proband chromosomes (frequency: 0.001) from Danish, Korean, and American individuals or families with breast and ovarian cancers, and was identified in 5 of 7138 (freq. 0.001) control chromosomes from healthy individuals (Bergthorsson 2001, Kim 2006, McKean-Cowdin 2005). The variant was identified in dbSNP (ID: rs28897693) as “Other”, Fanconi Anemia Mutation Database-LOVD (8x as unknown or unclassified), the ClinVar and Clinvitae databases (conflicting interpretations, classification benign by GeneDx and Invitae, likely benign by Counsyl, Ambry Genetics, and CHEO, and uncertain significance by BIC), GeneInsight COGR database (4x, classified as benign and likely benign by clinical laboratories), the BIC database (4x with unknown clinical importance, classification pending), and UMD (89x with a “likely neutral” classification). In UMD the variant was identified with co-occurring pathogenic BRCA1 variants (c.4065_4068delTCAA, p.Asn1355LysfsX10 and c.68_69delAG, p.Glu23ValfsX17), and BRCA2 variant (c.3847_3848delGT, p.Val1283LysfsX2), increasing the likelihood that the p.Gln1604Gln variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 7 of 5000 chromosomes (frequency: 0.0014); HAPMAP-EUR in 2 of 1006 chromosomes (frequency: 0.002), and HAPMAP-SAS in 5 of 978 chromosomes (frequency: 0.005); the NHLBI GO Exome Sequencing Project in 12 of 8600 European American alleles and in 6 of 4406 African American alleles; the genome Aggregation Database (February 27, 2017) in 294 (5 homozygous) of 282582 chromosomes (freq. 0.001); and the Exome Aggregation Consortium database (August 8th 2016) in 156 (2 homozygous) of 121402 chromosomes (freq. 0.001) in the following populations: Other in 5 of 908 chromosomes (freq. 0.006), South Asian in 71 of 16512 chromosomes (freq. 0.004), European (Non-Finnish) in 67 of 66738 chromosomes (freq. 0.001), African in 7 of 10406 chromosomes (freq. 0.0006), and East Asian in 4 of 8654 chromosomes (freq. 0.0005), Latino in 2 of 11570 chromosomes (freq. 0.0002) but was not seen in Finnish population; increasing the likelihood this could be a low frequency benign variant. The variant was (also) identified by our laboratory in 1 individual with breast cancer. The p.Gln1604Gln 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, only 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, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000112404 SCV000733605 benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
True Health Diagnostics RCV000162689 SCV000805233 likely benign Hereditary cancer-predisposing syndrome 2018-04-25 no assertion criteria provided clinical testing

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