Submissions for variant NM_058216.3(RAD51C):c.869T>C (p.Ile290Thr)

gnomAD frequency: 0.00001  dbSNP: rs749645694

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236194	SCV000293729	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of breast cancer (Osorio et al., 2012); This variant is associated with the following publications: (PMID: 21537932, 25470109, 14704354, 22451500)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524726	SCV000650027	uncertain significance	Fanconi anemia complementation group O	2024-06-06	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 290 of the RAD51C protein (p.Ile290Thr). This variant is present in population databases (rs749645694, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 21537932, 35451682). ClinVar contains an entry for this variant (Variation ID: 246254). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51C protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV000575382	SCV000674688	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-29	criteria provided, single submitter	clinical testing	The p.I290T variant (also known as c.869T>C), located in coding exon 6 of the RAD51C gene, results from a T to C substitution at nucleotide position 869. The isoleucine at codon 290 is replaced by threonine, an amino acid with similar properties. This alteration was reported in one family with familial breast cancer (Romero A et al. Breast Cancer Res. Treat., 2011 Oct;129:939-46). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000575382	SCV000909735	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004567779	SCV005053978	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-11-23	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004567779	SCV005689241	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2024-11-21	criteria provided, single submitter	clinical testing	The RAD51C c.869T>C (p.Ile290Thr) missense change has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with breast cancer (PMID: 21537932). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.