ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7188G>T (p.Leu2396Phe) (rs587780871)

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Total submissions: 9
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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) RCV001003381 SCV001161530 benign Breast-ovarian cancer, familial 2 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 = 0.000184
Ambry Genetics RCV000130352 SCV000185203 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
GeneDx RCV000160128 SCV000210417 likely benign not specified 2015-09-25 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160128 SCV000600736 likely benign not specified 2016-04-26 criteria provided, single submitter clinical testing
Invitae RCV000543885 SCV000635562 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 2396 of the BRCA2 protein (p.Leu2396Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs587780871, ExAC 0.02%). This variant has been reported in individuals undergoing genetic testing for hereditary cancer (PMID: 17924331). ClinVar contains an entry for this variant (Variation ID: 141729). Based on a multifactorial likelihood algorithm using genetic and statistical data, this variant has been determined to have a low probability of being pathogenic (PMID: 17924331, 21990134). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758944 SCV000887905 likely benign not provided 2017-10-26 criteria provided, single submitter clinical testing
Color RCV000130352 SCV000906546 likely benign Hereditary cancer-predisposing syndrome 2018-05-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000160128 SCV001160520 uncertain significance not specified 2019-04-25 criteria provided, single submitter clinical testing The BRCA2 c.7188G>T; p.Leu2396Phe variant (rs587780871), also known as 7416G>T, is reported in the literature as not pathogenic based on likelihood ratios considering family history and co-occurrence with a known pathogenic variant (Easton 2007, Lindor 2012). This variant is reported in ClinVar (Variation ID: 141729), but is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 2396 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Leu2396Phe 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. 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.
Integrated Genetics/Laboratory Corporation of America RCV000160128 SCV001361805 uncertain significance not specified 2019-12-09 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7188G>T (p.Leu2396Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251290 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7188G>T has been reported in the literature in individuals affected with breast cancer and acute lymphoblastic leukemia (Hwang 2018, Kim_2019, Zhang 2015). These reports does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. In addition, multifactorial probability models, performing systematic assessment of variants of unknown significance in the BRCA genes, which includes 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 likely neutral (Easton 2007, Lindor 2012). Co-occurrence with a pathogenic variant has been internally reported (BRCA1 c.5497G>A, p.Val1833Met), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions (evaluation after 2014) cite the variant as likely benign (n=3) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence of clinical and functional importance becomes available.

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