ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2597G>A (p.Arg866His) (rs80356911)

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Total submissions: 13
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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) RCV000077524 SCV001161507 benign Breast-ovarian cancer, familial 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
Invitae RCV000047893 SCV000075906 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 866 of the BRCA1 protein (p.Arg866His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs80356911, ExAC 0.01%). This variant has been observed in families with breast and/or ovarian cancer (PMID: 18273839, 25948282, 24504028). ClinVar contains an entry for this variant (Variation ID: 54613). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000130531 SCV000185400 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-24 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 reported in several cohorts of breast and ovarian cancer patients (Kluska A et al. BMC Med Genomics, 2015 May;8:19; Cunningham JM et al. Sci Rep, 2014 Feb;4:4026). 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 (Anczuk&oacute;w O et al. Genes Chromosomes Cancer, 2008 May;47:418-26). A different alteration at the same codon, p.R866C (c.2596C>T), has been classified as not pathogenic or of no clinical significance (p<0.01) by multifactorial analysis (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 1 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000589478 SCV000566693 uncertain significance not provided 2021-02-01 criteria provided, single submitter clinical testing Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Anczukow 2008, Cunningham 2014, Kluska 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as 2716G>A; This variant is associated with the following publications: (PMID: 31131967, 32846166, 28993434, 24504028, 18273839, 25528188, 12938098, 20104584, 15385441, 25348012, 25948282, 23893897)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589478 SCV000698968 uncertain significance not provided 2016-07-25 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2597G>A (p.Arg866His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. Arg866 is conserved across species but is not located in a known functional domain of the Breast cancer type 1 susceptibility protein. This variant was found in 4/121324 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in multiple breast or ovarian cancer patients without strong evidence for causality (i.e. co-segregation or functional studies). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS, without evidence to independently evaluate. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Mendelics RCV000047893 SCV000839268 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 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 Health, Inc RCV000130531 SCV000904129 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-19 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001661900 SCV001878257 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
Sharing Clinical Reports Project (SCRP) RCV000077524 SCV000109325 uncertain significance Breast-ovarian cancer, familial 1 2009-05-28 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077524 SCV000144487 uncertain significance Breast-ovarian cancer, familial 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.

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