ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9253A>C (p.Thr3085Pro) (rs397507423)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587457 SCV000523999 likely benign not provided 2019-10-18 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28591715)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000439515 SCV000602829 likely benign not specified 2016-11-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509957 SCV000608022 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-12 criteria provided, single submitter clinical testing The p.T3085P variant (also known as c.9253A>C), located in coding exon 23 of the BRCA2 gene, results from an A to C substitution at nucleotide position 9253. The threonine at codon 3085 is replaced by proline, an amino acid with highly similar properties. This alteration has been reported in multiple individuals <span style="font-family:arial,helvetica,sans-serif">on<span style="font-family:arial,helvetica,sans-serif"> the same chromosome (in cis) as the c.9235delG​ BRCA2 mutation (Ambry internal data). This amino acid position is poorly 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 RCV000557691 SCV000635726 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-05 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 3085 of the BRCA2 protein (p.Thr3085Pro). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and proline. This variant is present in population databases (rs397507423, ExAC 0.009%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 38224). 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 proline amino acid residue is 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 and their clinical significance is uncertain. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587457 SCV000695223 likely benign not provided 2016-06-09 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.9253A>C (p.Thr3085Pro) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome. This variant was found in 1/119814 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been found to co-occur in cis with a pathogenic mutation BRCA2 c.9235delG (p.Val3079PhefsX4) in an LCA sample, suggesting the benign role of the variant. One clinical diagnostic laboratories/reputable databases classified this variant as a VUS. 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. 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 RCV000509957 SCV000908252 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587457 SCV001133971 uncertain significance not provided 2019-06-26 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031807 SCV000054415 uncertain significance Breast-ovarian cancer, familial 2 2009-01-08 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000031807 SCV000592266 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The p.Thr3085Pro variant was not identified in the literature. This residue is not conserved in mammals and the variant residue proline (Pro) is found in opossum, increasing the likelihood this variant does not have clinical significance. Furthermore, computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In addition, this variant was identified in the presence of a co-occuring pathogenic variant in this individual, increasing the likelihood this variant is benign. In summary, base on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.

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