ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.539T>C (p.Ile180Thr) (rs80358761)

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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 RCV000132009 SCV000187068 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Breast Cancer Information Core (BIC) (BRCA2) RCV000083116 SCV000147092 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
GeneDx RCV000074539 SCV000108624 uncertain significance not provided 2017-05-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.539T>C at the cDNA level, p.Ile180Thr (I180T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). Using alternate nomenclature, this variant would be defined as BRCA2 767T>C. While this variant has been shown to not result in cryptic splicing via a minigene reporter assay, functional assays assessing protein function have not, to our knowledge, been completed (Di Giacomo 2013). BRCA2 Ile180Thr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ile180Thr occurs at a position that is conserved across species and is not located in a known functional domain. 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 Ile180Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000044650 SCV000072663 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 180 of the BRCA2 protein (p.Ile180Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in one individual in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51853). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Furthermore, this variant was shown to have no effect on mRNA splicing in a functional study analyzing the effect of missense variants on exon 7 splicing (PMID: 23983145). 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.
Sharing Clinical Reports Project (SCRP) RCV000083116 SCV000115190 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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