Submissions for variant NM_058216.3(RAD51C):c.414G>C (p.Leu138Phe)

gnomAD frequency: 0.00001  dbSNP: rs267606999

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129800	SCV000184611	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-11-07	criteria provided, single submitter	clinical testing	The p.L138F variant (also known as c.414G>C), located in coding exon 3 of the RAD51C gene, results from a G to C substitution at nucleotide position 414. The leucine at codon 138 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was previously described and found to co-segregate in one German breast and ovarian cancer family, and LOH was present in 3/3 tumors available (2 ovarian cancers and 1 breast cancer) (Meindl A et al. Nat. Genet. 2010 May; 42(5):410-4). This variant has been shown to be functionally impaired in DNA repair-related assays (Meindl A et al. Nat. Genet. 2010 May; 42(5):410-4; Somyajit K et al. J. Biol. Chem. 2012 Jan; 287(5):3366-80; Park JY et al. Oncogene 2014 Oct; 33(40):4803-12; Somyajit K et al. Carcinogenesis 2015 Jan; 36(1):13-24; Somyajit K et al. Nucleic Acids Res. 2015 Nov; 43(20):9835-55). This alteration was also reported in a Spanish female diagnosed with ovarian cancer at age 62; one of her sisters was diagnosed with breast cancer at age 37 and a second sister, who also had this variant, was diagnosed with bilateral breast cancer at ages 64 and 72. The variant was not reported in 550 healthy controls with no family history of cancer (Osorio A et al. Hum. Mol. Genet. 2012 Jul; 21(13):2889-98). This amino acid position is highly conserved on sequence alignment. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000648269	SCV000770083	likely pathogenic	Fanconi anemia complementation group O	2024-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 138 of the RAD51C protein (p.Leu138Phe). This variant is present in population databases (rs267606999, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 20400964, 22451500, 22538716, 27328445). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6825). 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%. Experimental studies have shown that this missense change affects RAD51C function (PMID: 20400964, 22167183, 24141787, 25292178, 26354865). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl	RCV000662981	SCV000785964	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2018-01-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129800	SCV000909442	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 138 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). Multiple functional studies have shown that the mutant protein exhibits significantly reduced ability to bind BRCA2, RAD51D, RAD51B, and XRCC3, reduced homologous recombination activity, and inability to complement RAD51C deficiency in cell survival assay (PMID: 20400964, 22167183, 24141787, 25292178, 36099300). This variant has been reported in five unrelated individuals affected with ovarian cancer with family history of ovarian cancer and/or breast cancer (PMID: 20400964, 22451500, 24993905, 35565380). This variant has also been reported in an individual with sporadic, early-onset ovarian cancer (PMID: 35565380) and in an individual with triple-negative breast cancer (PMID: 27328445). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
GeneDx	RCV001195017	SCV001787595	pathogenic	not provided	2023-03-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: impaired response to DNA damage, reduced RAD51 foci formation, impaired protein interaction with RAD51 paralogs, increased chromosome aberrations, and inability to rescue cell survival (Meindl et al., 2010; Somyajit et al., 2012; Somyajit et al., 2013; Prakash et al., 2022); Observed in individuals with history consistent with pathogenic variants in this gene (Loveday et al., 2012; Osorio et al., 2012; Spugnesi et al., 2016); 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; This variant is associated with the following publications: (PMID: 20952512, 27328445, 22451500, 25470109, 20400964, 29922827, 28888541, 26678223, 24993905, 26354865, 22167183, 23438602, 24141787, 21537932, 28829762, 30612635, 25292178, 22538716, 35565380, 14704354, 36562461, 36099300)
Revvity Omics, Revvity	RCV000648269	SCV002019013	likely pathogenic	Fanconi anemia complementation group O	2021-06-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000662981	SCV002811718	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2022-04-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000007227	SCV004017735	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-04-06	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22167183]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20400964, 24993905].
Baylor Genetics	RCV000007227	SCV004208005	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-05-15	criteria provided, single submitter	clinical testing
OMIM	RCV000007227	SCV000027423	risk factor	Breast-ovarian cancer, familial, susceptibility to, 3	2010-05-01	no assertion criteria provided	literature only
Leiden Open Variation Database	RCV001195017	SCV001365257	pathogenic	not provided	2014-11-02	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.