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
Color RCV000129817 SCV000911808 likely benign Hereditary cancer-predisposing syndrome 2017-04-04 criteria provided, single submitter clinical testing
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
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
Integrated Genetics/Laboratory Corporation of America RCV000587564 SCV000695100 uncertain significance not provided 2017-03-13 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7759C>T (p.Leu2587Phe) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the functional helical domain of the protein and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in the large control population database ExAC at a frequency of 0.0000412 (5/121430 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as a variant of uncertain significance. In addition, a publication postulated that the variant may be a risk allele in familial colorrectal cancer type X (FCCX) because of segregation with disease in a family and lack of mutation/rearrangement found in MLH1, MSH2, and MSH6 in the same family. However, the PMS2 gene was not analyzed, which may be responsible for the FCCX within the family. Taken together, this variant is classified as a VUS until more definitive information becomes available.
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.
True Health Diagnostics RCV000129817 SCV000805246 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-06 no assertion criteria provided clinical testing

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