ClinVar Miner

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

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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 RCV000166222 SCV000217001 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing The p.T10A variant (also known as c.28A>G), located in coding exon 1 of the BRCA2 gene, results from an A to G substitution at nucleotide position 28. The threonine at codon 10 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000470603 SCV000549561 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-08-31 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 (ExAC no frequency). This variant has been observed in an individual referred for BRCA2 testing (PMID: 27633797). However, at least one individual also carried a different variant in BRCA2 that has been determined to be pathogenic. Therefore, the clinical significance of this variant (c.28A>G) is unclear. In this literature, due to an apparent typographical error, these variants are indicated to occur in BRCA1 instead of BRCA2. ClinVar contains an entry for this variant (Variation ID: 186603). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). Experimental studies have shown that this variant does not affect mRNA splicing (PMID: 31843900). 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.
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Color Health, Inc RCV000166222 SCV000903898 likely benign Hereditary cancer-predisposing syndrome 2016-06-23 criteria provided, single submitter clinical testing
King Laboratory,University of Washington RCV001171391 SCV001251292 benign not specified 2019-09-01 no assertion criteria provided research

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