ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7759C>T (p.Leu2587Phe) (rs56335340)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129817 SCV000184631 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000587564 SCV000210446 uncertain significance not provided 2018-12-31 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7759C>T at the cDNA level, p.Leu2587Phe (L2587F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). Using alternate nomenclature, this variant would be defined as BRCA2 7987C>T. This variant was observed in several individuals with a personal and family history of colorectal cancer as well as two individuals with a personal and/or family history of breast and/or ovarian cancer (Infante 2006, Garre 2015, Esteban-Jurado 2016, Zutini 2018). BRCA2 Leu2587Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Leu2587Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Predisposition to Colorectal Cancer Group,Institut d’Investigacions Biomediques August Pi i Sunyer RCV000416750 SCV000262600 likely pathogenic Carcinoma of colon 2015-11-01 criteria provided, single submitter clinical testing Variant detected by whole exome sequencing in a family presenting aggregation mainly for colorectal cancer but also for gastric cancer
Invitae RCV000229398 SCV000283323 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-23 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 2587 of the BRCA2 protein (p.Leu2587Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs56335340, ExAC 0.007%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 15937982, 16758124), and an individual affected with colon and kidney cancer (PMID: 24814045). This variant has also been observed in individuals affected with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333), however, in one of these individuals a pathogenic allele was also identified in BRCA1, which suggests that this c.7759C>T variant was not the primary cause of disease. This variant is also known as 7987C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 141335). Experimental studies have shown that this missense change does not disrupt BRCA2 protein function (PMID: 29394989). 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.
Counsyl RCV000411503 SCV000487796 uncertain significance Breast-ovarian cancer, familial 2 2015-12-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000160141 SCV000592140 uncertain significance not specified 2016-07-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000160141 SCV000695100 uncertain significance not specified 2019-03-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7759C>T (p.Leu2587Phe) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain of 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 4.1e-05 in 246296 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (4.1e-05 vs 0.00075), allowing no conclusion about variant significance. This variant has been reported in the literature in individuals affected with breast cancer and colorectal cancer (Velasco_2005, Garre_2014). Garre_2014 reports a family affected with colorectal cancer in which the affected father and son carried the variant, while the affected mother did not. However, the authors did not evaluate PMS2 for causal variants. LOVD shared database reports the variant to co-occur with a pathogenic BRCA1 variant, c.2197_2201delGAGAA (p.Glu733fsX5). In addition, a functional study, Guidugli_2018, assessed HDR activity and found the variant to act comparable to wild type and authors classified the variant as neutral. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) predominantly cite the variant as uncertain significance (6x) and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Color RCV000129817 SCV000911808 likely benign Hereditary cancer-predisposing syndrome 2017-04-04 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000129817 SCV000805246 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-06 no assertion criteria provided clinical testing

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