Submissions for variant NM_007294.4(BRCA1):c.2597G>A (p.Arg866His)

gnomAD frequency: 0.00001  dbSNP: rs80356911

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)	RCV000077524	SCV001161507	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	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 = 0.000574
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047893	SCV000075906	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130531	SCV000185400	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-04	criteria provided, single submitter	clinical testing	The p.R866H variant (also known as c.2597G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 2597. The arginine at codon 866 is replaced by histidine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Cunningham JM et al. Sci Rep, 2014 Feb;4:4026; Kluska A et al. BMC Med Genomics, 2015 May;8:19; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190; Van der Merwe NC et al. Front Genet, 2022 Apr;13:834265). However, it has been detected in 0/2575 unselected patients with breast cancer and in 1/2809 healthy control individuals from a Malaysian cohort (Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103). This variant was tested in a minigene assay and showed normal splicing (Anczuków O et al. Genes Chromosomes Cancer, 2008 May;47:418-26). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077524	SCV000195908	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000589478	SCV000566693	uncertain significance	not provided	2023-07-26	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Anczukow et al., 2008; Cunningham et al., 2014; Kluska et al., 2015; Van der Merwe et al., 2022; Guindalini et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2716G>A; This variant is associated with the following publications: (PMID: 25948282, 15385441, 23893897, 25348012, 20104584, 12938098, 25528188, 18273839, 24504028, 28993434, 32846166, 34218100, 35464868, 33087888, 31131967, 15343273, 35264596)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488368	SCV000698968	uncertain significance	not specified	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2597G>A (p.Arg866His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251054 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2597G>A has been reported in the literature in individuals affected with breast and/or ovarian cancer without strong evidence for causality (e.g. Meyer_2003, Anczukow_2008, Cunningham_2014, Kluska_2015, Yildiz Tacar_2020, Combrink_2021, Guindalini_2022, Van der Merwe_2022) and also in a healthy control individual in a cohort of Asian individuals with and without breast cancer (Wen_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A study performing a multifactorial likelihood analysis based on collected research and clinical data has classified the variant as benign (Parsons_2019). Additionally, one clinical lab reported the variant in an ovarian cancer patient who also carried a co-occurring pathogenic BRCA2 variant, providing support for a benign role (Invitae via ClinVar). The following publications have been ascertained in the context of this evaluation (PMID: 18273839, 34218100, 24504028, 35264596, 25948282, 12938098, 31112341, 15385441, 35464868, 28993434, 32846166). Nine submitters, including the expert panel ENIGMA, have cited clinical-significance assessments for this variant to ClinVar after 2014. Five submitters classified the variant as uncertain significance, three submitters (including the expert panel) classified it as benign/likely benign and one classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics	RCV000047893	SCV000839268	benign	Hereditary breast ovarian cancer syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589478	SCV000887648	uncertain significance	not provided	2019-03-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130531	SCV000904129	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 866 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with breast cancer (PMID: 18273839, 25948282, 32846166, 34218100), an individual affected with ovarian cancer (PMID: 24504028) and in a breast cancer case-control meta-analysis in 4/60466 cases and 5/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001643). A multifactorial analysis has reported likelihood ratios for pathogenicity of 1.1768 and 0.0239 based on co-occurrence and family history, respectively (PMID: 31131967). This variant has been identified in 5/282454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000047893	SCV002025976	likely pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130531	SCV002538139	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-20	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492381	SCV004240254	uncertain significance	Breast and/or ovarian cancer	2022-12-20	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003488368	SCV004242831	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077524	SCV004815675	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 866 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with breast cancer (PMID: 18273839, 25948282, 32846166, 34218100), an individual affected with ovarian cancer (PMID: 24504028) and in a breast cancer case-control meta-analysis in 4/60466 cases and 5/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001643). A multifactorial analysis has reported likelihood ratios for pathogenicity of 1.1768 and 0.0239 based on co-occurrence and family history, respectively (PMID: 31131967). This variant has been identified in 5/282454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP)	RCV000077524	SCV000109325	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2009-05-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077524	SCV000144487	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000589478	SCV001550930	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Arg866His variant was identified in 3 of 8500 proband chromosomes (frequency: 0.0004) from American, Polish, German and Malaysian individuals or families with breast or ovarian cancer and was present in 1 of 5618 control chromosomes (frequency:0.0002) from healthy individuals (Cunningham 2014, Kluska 2015, Meyer 2003, Wen 2018). In a functional study using a minigene assay to look at the splicing effect of BRCA1 exon 11 unclassified variants, the variant did not show an effect on splicing (Anczuków 2008). The variant was identified in dbSNP (ID: rs80356911) “With Uncertain significance allele”, ClinVar (classified as uncertain significance; submitters: Ambry Genetics, GeneDx, Invitae, SCRP, BIC, Michigan Medical Genetics Laboratories (University of Michigan), Integrated Genetics Laboratory Corporation of America, Mendelics and Quest Diagnostics Nichols Institute San Juan Capistrano), LOVD 3.0, and UMD-LSDB (classified 3-UV). The variant was identified in control databases in 5 of 276800 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 1 of 24024 chromosomes (freq: 0.00004), European Non-Finnish in 3 of 126552 chromosomes (freq: 0.00002), and South Asian in 1 of 30766 chromosomes (freq: 0.00003) while not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and European Finnish populations. The p.Arg866 residue is 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.