ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4653T>C (p.Ser1551=) (rs587780863)

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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) RCV000211015 SCV000578353 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/).
GeneDx RCV000123924 SCV000167308 benign not specified 2014-02-03 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000211015 SCV000195931 benign Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163077 SCV000213578 likely benign Hereditary cancer-predisposing syndrome 2015-03-02 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 RCV001086793 SCV000289806 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000211015 SCV000489249 likely benign Breast-ovarian cancer, familial 1 2016-09-11 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163077 SCV000688509 likely benign Hereditary cancer-predisposing syndrome 2017-09-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586022 SCV000699161 likely benign not provided 2017-01-18 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4653T>C (p.Ser1551Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing, which is supported by the minigene-based splicing assay results in Houdayer et al 2012. This variant was found in 3/121366 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001284904 SCV001471000 likely benign none provided 2019-12-12 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355545 SCV001550464 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Ser1551= variant was identified in the literature; however the frequency of this variant in an affected population was not provided (Houdayer 2012, Judkins 2005). The variant was also identified in dbSNP (ID: rs587780863) as With Likely benign allele, ClinVar (as likely benign by ENIGMA, Color, Integrated Genetics, Ambry Genetics, Invitae, and Counsyl; and as benign by GeneDx and Michican Medical Genetics Laboratories), LOVD 3.0 (as benign and as VUS). The variant was identified in control databases in 7 of 277012 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (Non-Finnish) population in 7 of 126516 chromosomes (freq: 0.000055), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ser1551= 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) 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.

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