Submissions for variant NM_058216.3(RAD51C):c.154A>C (p.Ile52Leu)

gnomAD frequency: 0.00001  dbSNP: rs730881927

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160918	SCV000211622	uncertain significance	not provided	2024-10-07	criteria provided, single submitter	clinical testing	Observed in 1 out of 427 cancer-free control subjects but was not found among 1,655 women with a personal history of breast and/or ovarian cancer (PMID: 21990120); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21990120)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198840	SCV000255186	uncertain significance	Fanconi anemia complementation group O	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 52 of the RAD51C protein (p.Ile52Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 182830). 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	RCV000563190	SCV000667110	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-10	criteria provided, single submitter	clinical testing	The p.I52L variant (also known as c.154A>C), located in coding exon 2 of the RAD51C gene, results from an A to C substitution at nucleotide position 154. The isoleucine at codon 52 is replaced by leucine, an amino acid with highly similar properties. This variant was previously detected in 0/1388 hereditary breast and/or ovarian cancer families and 1/427 controls (Thompson et al. Hum. Mutat. 2012; 33: 95-9). 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	RCV000563190	SCV000906586	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 52 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature and has been observed in one unaffected control individual (PMID: 21990120). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV003462104	SCV004207920	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2024-03-21	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001195011	SCV001365246	likely benign	not specified	2011-08-25	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Ian Campbell.