ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5538G>A (p.Gln1846=) (rs80356849)

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Total submissions: 10
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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) RCV000112700 SCV000578244 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/).
Invitae RCV001081545 SCV000077056 likely benign Hereditary breast and ovarian cancer syndrome 2020-09-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000164404 SCV000215040 likely benign Hereditary cancer-predisposing syndrome 2014-10-22 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588004 SCV000699271 likely benign not provided 2016-03-22 criteria provided, single submitter clinical testing Variant Summary: The BRCA1 c.5538G>A variant involves the alteration of a non-conserved nucleotide resulting in a synonymous change. 3/5 in silico tools via Alamut predict no significant effect on splicing. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0008% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.10%). The variant was reported in the literature in an individual who also carried a pathogenic BRCA1 variant on opposite allele (c.66_67delAG; Diez_2003), strongly suggesting the benign nature of the variant. Additionally, functional studies show the variant to have no effect on splicing (Houdayer_2012). Multiple reputable clinical labs have classified the variant as "likely benign." Therefore, this variant was classified as Likely Benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000496446 SCV001158864 likely benign not specified 2018-10-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164404 SCV001343399 likely benign Hereditary cancer-predisposing syndrome 2019-08-09 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112700 SCV000145573 uncertain significance Breast-ovarian cancer, familial 1 1997-03-11 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496446 SCV000587521 benign not specified 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353496 SCV000591639 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Gln1846Gln 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, and RNA analysis of the variant by Houdayer (2012) found no difference in splicing. The variant was identified in at least 3 of 113162 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer, and was not identified in 200 control chromosomes from healthy individuals (Diez_2003_12955716, Judkins_2005_16267036, Houdayer_2012_22505045); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant is listed in the dbSNP database (ID: rs80356849) “With Uncertain significance allele”, but frequency information was not available from the general population. The variant was also identified in the ClinVar database, LOVD, the BIC database (1X with unknown clinical importance), and the UMD (1X as a likely neutral variant). 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 predicted benign.
Brotman Baty Institute,University of Washington RCV000112700 SCV001242104 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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