ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2584A>G (p.Lys862Glu)

gnomAD frequency: 0.00001  dbSNP: rs80356927
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Total submissions: 18
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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) RCV000031057 SCV000244324 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 = 0.00000991
Labcorp Genetics (formerly Invitae), Labcorp RCV001084418 SCV000075900 benign Hereditary breast ovarian cancer syndrome 2024-01-10 criteria provided, single submitter clinical testing
GeneDx RCV000758799 SCV000108659 likely benign not provided 2019-06-27 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21990134, 16518693, 22753008, 17924331, 26306726, 16267036, 23893897, 18273839, 25682074, 18951461, 18779604, 15385441, 25348012, 29453630)
Ambry Genetics RCV000162978 SCV000213466 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 RCV000162978 SCV000537503 likely benign Hereditary cancer-predisposing syndrome 2015-11-25 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000074574 SCV000593691 likely benign not specified 2017-04-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758799 SCV000887646 likely benign not provided 2023-07-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000074574 SCV000918734 benign not specified 2019-09-26 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2584A>G (p.Lys862Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251066 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (6e-05 vs 0.001), allowing no conclusion about variant significance. c.2584A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, however these reports do not provide evidence for pathogenicity (Judkins_2005, Wong-Brown_2015, Anczukow_2008, Kurian_2008, Minucci_2015, Peyrat_1998, Li_2018, Kraemer_2019). In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton 2007 and Lindor 2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters, including one expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign while the expert panel has classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798028 SCV002043433 likely benign Breast and/or ovarian cancer 2021-04-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000758799 SCV002049438 uncertain significance not provided 2021-11-09 criteria provided, single submitter clinical testing The BRCA1 c.2584A>G; p.Lys862Glu variant (rs80356927) is reported in the literature in individuals affected with breast and/or ovarian cancer, although it was no demonstrated to be disease-causing (Peyrat 1998). This variant is reported as benign or likely benign by multiple laboratories in ClinVar (Variation ID: 37476), and it is found in the general population with an overall allele frequency of 0.01% (16/282472 alleles) in the Genome Aggregation Database. The lysine at codon 862 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.808). However, multifactorial likelihood analysis considering family history of disease, co-occurrence with pathogenic variants, and co-segregation with disease suggest this variant has very low odds of causing disease (Easton 2007, Lindor 2012). However, given the lack of clinical and functional data, the significance of the p.Lys862Glu variant is uncertain at this time. References: Easton DF et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007 Nov;81(5):873-83. PMID: 17924331. Lindor NM et al. A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Hum Mutat. 2012 Jan;33(1):8-21. PMID: 21990134 Peyrat JP et al. Germline BRCA1 mutations in patients from 84 families with breast and/or ovarian cancers in northern France. Eur J Cancer Prev. 1998 Feb;7 Suppl 1:S7-12. PMID: 10866029.
Sema4, Sema4 RCV000162978 SCV002538136 likely benign Hereditary cancer-predisposing syndrome 2021-06-22 criteria provided, single submitter curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV000031057 SCV004016763 benign Breast-ovarian cancer, familial, susceptibility to, 1 2023-07-07 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004554623 SCV004740207 likely benign BRCA1-related disorder 2019-09-24 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).
Sharing Clinical Reports Project (SCRP) RCV000031057 SCV000053652 benign Breast-ovarian cancer, familial, susceptibility to, 1 2010-02-10 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031057 SCV000144481 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357913 SCV001553513 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Lys862Glu variant was identified in 8 of 111260 proband chromosomes (frequency: 0.00007) from individuals or families with breast cancer (Judkins 2005). The variant was also identified in dbSNP (ID: rs80356927) as “With Likely benign allele”, Clinvitae database (classified as benign by ClinVar; classified as likely benign by ClinVar, Invitae), Fanconi Anemia Mutation Database (LOVD), ARUP Laboratories BRCA Mutations Database (classified as not pathogenic or of no clinical significance), the ClinVar database (classified as benign by ENIGMA, Ambry genetics, SCRP; classified as likely benign by Invitae, GeneDx; classified as uncertain significance by BIC), the BIC database (5x with unknown clinical importance), and UMD (12x with a “likely neutral” classification). This variant was identified in the Exome Aggregation Consortium database (August 8th 2016) in 12 of 121328 chromosomes (freq. 0.0001) in the following populations: European in 8 of 66696 chromosomes (freq. 0.0001), Asian in 3 of 16502 chromosomes (freq. 0.0002), Finnish in 1 of 6614 chromosomes (freq. 0.0002), but was not seen in African, Latino and Other populations. The p.Lys862 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was also classified as neutral with odds in favor of neutrality 2059 in a study utilizing evidence of co-occurrence with a pathogenic variant, family history and if available segregation of the variant with disease (Easton 2007). The variant was also found to have a probability of being deleterious of 9.91×10−6 in a similar study (Lindor 2012). In addition, a study by Burk-Herrick (2005) found the variant has no effect by analyzing 19 marsupials and 94 eutherian mammal sequences, which were used to rank oncogenic risk of missence mutations based on conservation. 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000758799 SCV001905900 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000074574 SCV001957180 benign not specified no assertion criteria provided clinical testing

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