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

gnomAD frequency: 0.00019  dbSNP: rs55650082

Total submissions: 17

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, susceptibility to, 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 ovarian cancer syndrome	2024-01-31	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: seen in unaffected individuals, 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 Diagnostics, LLC DBA Color Health	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	2023-04-01	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
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798070	SCV002043426	likely benign	Breast and/or ovarian cancer	2020-03-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162685	SCV002538048	likely benign	Hereditary cancer-predisposing syndrome	2021-06-24	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001080273	SCV004014884	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554640	SCV004767460	likely benign	BRCA1-related disorder	2019-08-01	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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, susceptibility to, 1	2008-11-20	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077495	SCV000144184	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000077495	SCV000207339	likely benign	Breast-ovarian cancer, familial, susceptibility to, 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.