ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.455C>A (p.Thr152Lys) (rs80358691)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195370 SCV000072455 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 152 of the BRCA2 protein (p.Thr152Lys). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with unilateral breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 51674). An experimental study has shown that this missense change may disrupt a splicing enhancer, leading to skipping of exon 5 (PMID: 20215541). However, a follow-up study demonstrated that the BRCA2 transcript lacking exon 5 can also be found in cell lines that do not carry this variant, suggesting that it is a naturally-occurring alternative mRNA transcript (PMID: 27060066). 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: "Probably Damaging"; 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.
GeneDx RCV000588748 SCV000210241 uncertain significance not provided 2017-10-24 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.455C>A at the cDNA level, p.Thr152Lys (T152K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). This variant, also known as BRCA2 683C>A using alternate nomenclature, was observed in one individual with breast cancer (Borg 2010). Splicing functional minigene assays by Sanz et al. (2010) showed a splicing effect with partial skipping of exon 5, leading authors to classify this variant as uncertain. BRCA2 Thr152Lys was not observed in large population cohorts (Lek 2016). Since Threonine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Thr152Lys 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 Thr152Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000213276 SCV000276761 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000213276 SCV000688882 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588748 SCV000694780 uncertain significance not provided 2016-04-18 criteria provided, single submitter clinical testing Variant summary: The c.455C>A variant involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a pathogenic outcome. The variant is absent from the large, broad ExAC control population. The variant was reported in the literature in affected individuals, without strong evidence for causality. Additionally, a splicing assay showed the variant to result in partial exon 5 skipping (Sanz_2010), the outcome of which is unknown. Multiple reputable clinical labs have classified the variant was a VUS, while one classified it as "likely benign". Taken together, this variant was classified as a VUS until additional evidence becomes available.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113613 SCV000146890 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113613 SCV000189306 likely benign Breast-ovarian cancer, familial 2 2011-02-28 no assertion criteria provided clinical testing

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