Submissions for variant NM_058216.3(RAD51C):c.485G>A (p.Gly162Glu)

dbSNP: rs35151472

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205588	SCV000260716	uncertain significance	Fanconi anemia complementation group O	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 162 of the RAD51C protein (p.Gly162Glu). This variant is present in population databases (rs35151472, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 21990120). ClinVar contains an entry for this variant (Variation ID: 220285). 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 expected to disrupt RAD51C protein function with a positive 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	RCV000214777	SCV000273315	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-26	criteria provided, single submitter	clinical testing	The p.G162E variant (also known as c.485G>A), located in coding exon 3 of the RAD51C gene, results from a G to A substitution at nucleotide position 485. The glycine at codon 162 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in the literature in individuals diagnosed with breast and/or ovarian cancer (Thompson ER et al. Hum. Mutat. 2012 Jan;33:95-9). This variant was identified in 0/3447 cases of invasive epithelial ovarian cancer and in 1/4812 unaffected controls (Song H et al. J Clin Oncol, 2015 Sep;33:2901-7). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000679799	SCV000292962	likely pathogenic	not provided	2023-07-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: defective homology-directed repair activity, cisplatin and olaparib sensitivity, and impaired binding to RAD51B, RAD51D, and XRCC3 (Hu et al., 2023; Prakash et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with a personal and/or family history of breast and/or ovarian cancer for whom previous BRCA1/2 testing was negative (Thompson et al., 2012); This variant is associated with the following publications: (PMID: 25470109, 25086635, 26261251, 23117857, 28829762, 21537932, 14704354, 36099300, 21990120, 37253112)
Color Diagnostics, LLC DBA Color Health	RCV000214777	SCV000691240	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-19	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 162 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 21990120). This variant has also been reported in a healthy control individual (PMID: 26261251). This variant has been identified in 1/251482 chromosomes 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.
PreventionGenetics, part of Exact Sciences	RCV000679799	SCV000807172	uncertain significance	not provided	2017-06-08	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000679799	SCV001365262	uncertain significance	not provided	2011-08-25	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Ian Campbell.