ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3154G>A (p.Ala1052Thr) (rs730881520)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567319 SCV000668808 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000567319 SCV000903460 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
GeneDx RCV000589646 SCV000210306 uncertain significance not provided 2014-09-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3154G>A at the cDNA level, p.Ala1052Thr (A1052T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala1052Thr 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 Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ala1052Thr occurs at a position that is poorly conserved across species and accepts Threonine in several species. This variant 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 Ala1052Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589646 SCV000694669 uncertain significance not provided 2016-07-31 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3154G>A (p.Ala1052Thr) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured here due to low reliability) predicting a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP), nor has it been to our knowledge, reported in affected individuals via publications. An internal LCA specimen reports the variant to co-occur with a pathogenic BRCA1 variant, c.4484G>T (p.Arg1485Met - classified as pathogenic by LCA). A reputable clinical laboratory cites the variant as "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information.

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