ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2584A>G (p.Lys862Glu) (rs80356927)

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Total submissions: 11
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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 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
Invitae RCV001084418 SCV000075900 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000074574 SCV000108659 likely benign not specified 2017-11-03 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 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: 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 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 2020-07-23 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.
Sharing Clinical Reports Project (SCRP) RCV000031057 SCV000053652 benign Breast-ovarian cancer, familial 1 2010-02-10 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031057 SCV000144481 uncertain significance Breast-ovarian cancer, familial 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.

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