ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5423T>C (p.Ile1808Thr) (rs397507350)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217283 SCV000276364 likely benign Hereditary cancer-predisposing syndrome 2018-11-14 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign);Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000432442 SCV000517973 likely benign not specified 2017-12-06 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000587412 SCV000694868 uncertain significance not provided 2016-02-22 criteria provided, single submitter clinical testing Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of an medium size and hydrophobic Isoleucine (I) with a medium size and polar Threonine (T). 3/5 in silico tools predict the variant to be benign. It was found in the large and broad cohorts of the ExAC project at an allele frequency of 0.0024% which does not exceed the maximal expected allele frequency of a disease causing BRCA2 allele (0.075%). To our knowledge, the variant was not reported in patients and clinically relevant functional studies assessing the functional impact of the variant were not published either. One clinical diagnostic laboratory and one database classify variant as a VUS (without evidence to independently evaluate). Due to the lack of clinical data and functional studies, the variant was classified as a variant of uncertain significance until more information becomes available.
PreventionGenetics,PreventionGenetics RCV000587412 SCV000805723 uncertain significance not provided 2017-12-21 criteria provided, single submitter clinical testing
Invitae RCV000697860 SCV000826493 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1808 of the BRCA2 protein (p.Ile1808Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs397507350, ExAC 0.006%). This variant has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 37964). 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 threonine 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.
Color RCV000217283 SCV000911759 likely benign Hereditary cancer-predisposing syndrome 2017-11-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031545 SCV000054150 uncertain significance Breast-ovarian cancer, familial 2 2010-04-15 no assertion criteria provided clinical testing

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