ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.10070C>T (p.Thr3357Ile) (rs80358388)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130535 SCV000185404 uncertain significance Hereditary cancer-predisposing syndrome 2014-12-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),Other data supporting benign classification
GeneDx RCV000212292 SCV000210522 uncertain significance not provided 2014-08-15 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.10070C>T at the cDNA level, p.Thr3357Ile (T3357I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant was observed at least once in an individual whose personal and/or family history was presumably suspicious for hereditary breast and ovarian cancer syndrome (Olopade 2003). BRCA2 Thr3357Ile 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 Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Thr3357Ile occurs at a position that is variable across species and is not located in a known functional domain. 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 Thr3357Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000112834 SCV000784891 uncertain significance Breast-ovarian cancer, familial 2 2017-01-30 criteria provided, single submitter clinical testing
Color RCV000130535 SCV000905839 likely benign Hereditary cancer-predisposing syndrome 2016-01-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779914 SCV000916830 uncertain significance not specified 2017-11-03 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.10070C>T (p.Thr3357Ile) variant involves the alteration of a non-conserved nucleotide that leads to change in an evolutionarily non-conserved amino acid residue that is located at the C-terminal end of the protein that does not belong to any known functional domain. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). In addition, a truncation variant upstream of this position have been observed in the general population (with several homozygous occurrences) and classified as benign by our laboratory and others (c.9976A>T (p.Lys3326Ter)), suggesting that even the complete functional loss of this C-terminal protein part wouldnt lead to deleterious biological effects, though these predictions have not been confirmed by in vitro or in vivo functional studies. This variant was found in 1/30974 control chromosomes at a frequency of 0.0000323, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Breast Cancer Information Core (BIC) (BRCA2) RCV000112834 SCV000145746 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing

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