ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1789G>A (p.Glu597Lys) (rs55650082)

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Total submissions: 14
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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) RCV000077495 SCV000244307 benign Breast-ovarian cancer, familial 1 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000000000692
Invitae RCV001080273 SCV000075596 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000074567 SCV000108652 likely benign not specified 2018-02-18 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 RCV000162685 SCV000213139 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as 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.
Color Health, Inc RCV000162685 SCV000682984 likely benign Hereditary cancer-predisposing syndrome 2015-07-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000074567 SCV000698862 benign not specified 2020-11-24 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1789G>A (p.Glu597Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-05 in 252224 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (8.3e-05 vs 0.001), allowing no conclusion about variant significance. c.1789G>A has been reported in the literature in individuals affected with breast and/or ovarian cancer (example, Judkins_2005, Lee_2008, Easton_2007, Borg_2010, Capanu_2011, Spearman_2008, Alsop_2012, Lu_2012, Maxwell_2014, Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multifactorial probability models predict a neutral outcome (Lindor_2012). At-least one co-occurrence with another pathogenic variant has been reported in the BIC database (BRCA2 c.6373_6374insA, p.Thr2125?fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034728 SCV000888847 likely benign not provided 2018-06-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000074567 SCV001158823 likely benign not specified 2018-08-20 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001659931 SCV001878205 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034728 SCV000043180 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000077495 SCV000109293 likely benign Breast-ovarian cancer, familial 1 2008-11-20 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077495 SCV000144184 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000077495 SCV000207339 likely benign Breast-ovarian cancer, familial 1 2014-11-06 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354113 SCV001548646 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Glu597Lys variant was identified in 7 of 7414 proband chromosomes (frequency: 0.0009) from individuals or families with breast cancer (Goidescu 2017, Momozawa 2018, Johnston 2012, Borg 2010, Lee 2008) and was identified in 6 of 48666 chromosomes (frequency: 0) from healthy individuals. In silico prediction models looking at causality likelihood ratios and posterior probability suggest the variant is neutral/not pathogenic (Easton 2007, Lindor 2012). The variant was identified in dbSNP (ID: rs55650082) “With Pathogenic, other allele”, ClinVar (classified benign, reviewed by an expert panel (2015); submitters: benign by ENIGMA, Ambry Genetics; likely benign by Color, Integrated Genetics/Laboratory Corporation of America, Invitae, GeneDx, SCRP and Pathway Genomics; uncertain significance by BIC and Biesecker Lab/Human Development Section (NIH)), LOVD 3.0 (1x), BIC Database (16X with unknown clinical importance, pending classification) and ARUP Laboratories (classified as 1 - not pathogenic or of no clinical significance). The variant was not identified in UMD-LSDB database. The variant was also identified in control databases in 22 of 276862 chromosomes at a frequency of 0.00008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 3 of 23996 chromosomes (freq: 0.0001), European Non-Finnish in 18 of 126494 chromosomes (freq: 0.0001), and South Asian in 1 of 30778 chromosomes (freq: 0.00003) while not observed in the Other, Latino, Ashkenazi Jewish, East Asian and European Finnish populations. The p.Glu597 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 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. This variant is classified as a variant of uncertain significance.

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