Submissions for variant NM_000059.3(BRCA2):c.608C>A (p.Thr203Asn) (rs398122547)

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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	RCV000509879	SCV000608010	uncertain significance	Hereditary cancer-predisposing syndrome	2018-03-01	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color	RCV000509879	SCV000905901	uncertain significance	Hereditary cancer-predisposing syndrome	2018-06-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000758918	SCV000567749	uncertain significance	not provided	2018-08-24	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.608C>A at the cDNA level, p.Thr203Asn (T203N) at the protein level, and results in the change of a Threonine to an Asparagine (ACC>AAC). Using alternate nomenclature, this variant would be defined as BRCA2 836C>A. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Thr203Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Thr203Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000471187	SCV000549867	uncertain significance	Hereditary breast and ovarian cancer syndrome	2018-10-11	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with asparagine at codon 203 of the BRCA2 protein (p.Thr203Asn). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and asparagine. This variant is present in population databases (rs398122547, ExAC 0.001%) but has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 91437). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758918	SCV000887864	uncertain significance	not provided	2017-12-26	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000076954	SCV000108751	uncertain significance	Breast-ovarian cancer, familial 2	2012-09-04	no assertion criteria provided	clinical testing

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