ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.28A>G (p.Thr10Ala) (rs786203080)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166222 SCV000217001 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166222 SCV000903898 likely benign Hereditary cancer-predisposing syndrome 2016-06-23 criteria provided, single submitter clinical testing
GeneDx RCV000586386 SCV000572250 uncertain significance not provided 2016-11-07 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.28A>G at the cDNA level, p.Thr10Ala (T10A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). Using alternate nomenclature, this variant would be defined as BRCA2 256A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Thr10Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Thr10Ala occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Thr10Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586386 SCV000694644 uncertain significance not provided 2016-06-10 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.28A>G (p.Thr10Ala) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome. This variant was not found in approximately 119844 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. The variant has been classified as a VUS by one clinical lab and one database. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000470603 SCV000549561 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 10 of the BRCA2 protein (p.Thr10Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (rs786203080, ExAC no frequency). This variant has been observed in an individual referred for BRCA2 testing (PMID: 27633797). However, in that individual a pathogenic allele was also identified in BRCA2, which suggests that this c.28A>G variant was not the primary cause of disease. In this literature, due to an apparent typographical error, these variants are indicated to occur in BRCA1 instead of BRCA2. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.

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