ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7625C>T (p.Thr2542Met) (rs80358989)

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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 RCV000132470 SCV000187564 likely benign Hereditary cancer-predisposing syndrome 2017-02-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification
Color RCV000132470 SCV000903910 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000218699 SCV000592132 uncertain significance not specified 2014-04-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515343 SCV000611377 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3; Tracheoesophageal fistula 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000589734 SCV000279201 uncertain significance not provided 2016-01-02 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7625C>T at the cDNA level, p.Thr2542Met (T2542M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). Using alternate nomenclature, this variant has been previously published as BRCA2 7853C>T. This variant was observed in at least one hereditary breast/ovarian family and in an individual with late onset esophageal cancer (Capalbo 2006, Akbari 2008). BRCA2 Thr2542Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Thr2542Met occurs at a position that is not conserved and is located in the DNA binding domain and region of interaction with FANCD2 and SFM1/DSS1 (Borg 2010, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Thr2542Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589734 SCV000695087 uncertain significance not provided 2017-01-18 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7625C>T (p.Thr2542Met) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120478 control chromosomes. The variant has been reported in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000197583 SCV000254209 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 2542 of the BRCA2 protein (p.Thr2542Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with esophageal squamous cell carcinoma (PMID: 17724471). ClinVar contains an entry for this variant (Variation ID: 96854). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The methionine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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 RCV000589734 SCV000889137 uncertain significance not provided 2018-07-09 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000082975 SCV000115049 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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