Submissions for variant NM_002878.3(RAD51D):c.38C>T (p.Thr13Ile) (rs1064795830)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color	RCV000773179	SCV000906740	uncertain significance	Hereditary cancer-predisposing syndrome	2018-06-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000486273	SCV000572010	uncertain significance	not provided	2017-06-12	criteria provided, single submitter	clinical testing	This variant is denoted RAD51D c.38C>T at the cDNA level, p.Thr13Ile (T13I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Thr13Ile was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51D Thr13Ile occurs at a position where amino acids with properties similar to Threonine are tolerated across species and is located in the ssDNA and XRCC2 binding domains (Miller 2004, Kim 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether RAD51D Thr13Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000546552	SCV000651743	uncertain significance	Breast-ovarian cancer, familial 4	2017-04-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with isoleucine at codon 13 of the RAD51D protein (p.Thr13Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RAD51D-related disease. 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: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.