Submissions for variant NM_058216.3(RAD51C):c.784T>G (p.Leu262Val)

gnomAD frequency: 0.00014  dbSNP: rs149331537

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000585995	SCV000150088	uncertain significance	not provided	2024-06-20	criteria provided, single submitter	clinical testing	Observed in individuals with breast, ovarian, colon, or pancreatic cancer, but also in controls (PMID: 21990120, 24504028, 26261251, 26740214, 28767289, 28135145, 29522266, 30426508, 32659497, 33471991, 35039523); Published functional studies demonstrate normal homology-directed repair (HDR) activity in vitro (PMID: 37253112); In silico analysis supports a deleterious effect on splicing; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25470109, 23117857, 27527004, 29522266, 21990120, 26261251, 25086635, 28135145, 24504028, 26740214, 28767289, 32659497, 33471991, 31874108, 30426508, 26580448, 35980532, 35039523, 30306255, 32885271, 29416752, 14704354, 37253112)
Ambry Genetics	RCV000116179	SCV000214302	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-02	criteria provided, single submitter	clinical testing	The c.784T>G variant (also known as p.L262V), located in coding exon 5 of the RAD51C gene, results from a T to G substitution at nucleotide position 784. The leucine at codon 262 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Thompson ER et al. Hum. Mutat. 2012 Jan;33:95-9; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Jønson L et al. Breast Cancer Res. Treat. 2016 Jan;155:215-22; Hauke J et al. Cancer Med. 2018 04;7:1349-1358; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration has also been reported in an individual diagnosed with pancreatic cancer (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). Additionally, in a homology-directed DNA repair (HDR) assay, this alteration showed a functionally normal read-out (Hu C et al. Cancer Res, 2023 Aug;83:2557-2571). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect in the set of samples tested; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Based on the available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206074	SCV000260785	uncertain significance	Fanconi anemia complementation group O	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 262 of the RAD51C protein (p.Leu262Val). This variant is present in population databases (rs149331537, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, pancreatic cancer, colon cancer (PMID: 21990120, 26261251, 26740214, 28135145, 28767289, 35039523, 36099300). ClinVar contains an entry for this variant (Variation ID: 128210). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAD51C protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect RAD51C function (PMID: 37253112). Studies have shown that this missense change is associated with inconclusive levels of altered splicing (internal data). 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.
Counsyl	RCV000206074	SCV000489919	uncertain significance	Fanconi anemia complementation group O	2016-08-10	criteria provided, single submitter	clinical testing
Counsyl	RCV000411451	SCV000489920	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2016-08-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116179	SCV000537554	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 262 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has reported the mutant protein to exhibit normal interaction with its binding partners (PMID: 36099300). This variant has been reported in individuals affected with breast, ovarian, and pancreatic cancer (PMID: 21990120, 24504028, 26261251, 26740214, 28767289, 32659497, 35039523, 36099300), and with a pathogenic ATM co-variant in an individual affected with colon cancer (PMID: 28135145). This variant has also been reported in an unaffected individual in a case-control study of ovarian cancer (PMID: 26261251). In a large breast cancer case-control meta-analysis, this variant has been observed in 25/60441 cases and 13/53448 controls (OR=1.701, 95%CI 0.87 to 3.324, p-value=0.143; PMID: 33471991). This variant has been identified in 20/282828 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in 5 individuals age 70 years or older without cancer by FLOSSIES. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778711	SCV000699825	uncertain significance	not specified	2024-09-30	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.784T>G (p.Leu262Val) results in a conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 261730 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RAD51C causing Hereditary Breast And Ovarian Cancer Syndrome (5.7e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.784T>G has been reported in several patients with breast and/or ovarian cancer, colorectal cancer and pancreatic cancer (Thompson_2011, Cunningham_2014, Song_2015, Jonson_2016, Yurgelun_2017, Shindo_2017, etc), without clear evidence supporting pathogenicity. In a study (Song_2015), the variant was found to be slightly overrepresented in ovarian cases (4/3429) than in controls (1/2772). One internal case tested for inherited cancer panel also carried a pathogenic variant in ATM c.1339C>T (p.Arg447X). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25086635, 30306255, 24504028, 33471991, 32659497, 26740214, 23117857, 32885271, 31874108, 29416752, 30426508, 28767289, 26261251, 25470109, 21990120, 28135145). ClinVar contains an entry for this variant (Variation ID: 128210). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000765378	SCV000896644	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778506	SCV000914779	uncertain significance	RAD51C-related disorder	2017-09-07	criteria provided, single submitter	clinical testing	The RAD51C c.784T>G (p.Leu262Val) variant has been reported in three studies and is found in a heterozygous state in five individuals with cancer, all of whom were negative for variants in BRCA1/2 (Thompson et al. 2012; Song et al. 2015; Jonson et al. 2016). Four of the individuals had epithelial ovarian cancer and one male individual had prostate cancer. The p.Leu262Val variant was found in one of 6398 control chromosomes and is reported at a frequency of 0.000126 in the European (non-Finnish) population of the Genome Aggregation Database. Although this variant has not been reported in any individuals with Fanconi anemia, it is known that RAD51C heterozygous variants can also confer carrier status for Fanconi anemia. Based on the evidence, the p.Leu262Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for RAD51C-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics	RCV000206074	SCV001140721	uncertain significance	Fanconi anemia complementation group O	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000411451	SCV001428790	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2019-06-04	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000585995	SCV002010583	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798365	SCV002043693	uncertain significance	Breast and/or ovarian cancer	2021-05-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116179	SCV002530017	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001778711	SCV002551139	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411451	SCV004019659	likely benign	Breast-ovarian cancer, familial, susceptibility to, 3	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000411451	SCV004209757	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2024-03-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585995	SCV005623324	uncertain significance	not provided	2023-11-22	criteria provided, single submitter	clinical testing	The RAD51C c.784T>G (p.Leu262Val) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 26740214 (2016), 26261251 (2015), 24504028 (2014), 21990120 (2012)), pancreatic cancer (PMID: 32659497 (2020), 28767289 (2017), 28135145 (2017)), as well as in healthy controls (PMID: 26261251 (2015)). Additionally, the variant has been reported in a large-scale breast cancer association study, and was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51C)). The frequency of this variant in the general population, 0.00022 (11/50798 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on RAD51C mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV000778506	SCV000807179	uncertain significance	RAD51C-related disorder	2024-09-28	no assertion criteria provided	clinical testing	The RAD51C c.784T>G variant is predicted to result in the amino acid substitution p.Leu262Val. This variant has been reported as a variant of uncertain significance in multiple individuals with BRCA1/2-negative breast/ovarian cancer (for example, see Thompson et al. 2012. PubMed ID: 21990120; Cunningham et al. 2014. PubMed ID: 24504028; Lerner-Ellis et al. 2021. PubMed ID: 32885271) and one individual with pancreatic cancer (Shindo et al. 2017. PubMed ID: 28767289). However, it has also been reported in an individual with colorectal cancer who was heterozygous for pathogenic variants in the ATM and KRAS genes (Yurgelun et al. 2017. PubMed ID: 28135145). In vitro studies suggest that this variant does not significantly alter protein-protein interactions between RAD51C and its binding partners relative to wild type (Prakash et al. 2022. PubMed ID: 36099300). Additionally, this variant is predicted to generate a cryptic splice donor site by available in silico splicing prediction programs (Alamut Visual Plus v1.6.1; https://spliceailookup.broadinstitute.org/), but this has not been directly confirmed by functional studies or RNA sequencing analysis. This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128210/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Leiden Open Variation Database	RCV001195025	SCV001365277	uncertain significance	Ovarian neoplasm	2011-08-25	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Ian Campbell.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356788	SCV001552053	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51C p.Leu262Val variant was identified in 6 of 12090 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer and was present in 1 of 4854 control chromosomes (frequency: 0.0002) from healthy individuals (Jonson 2015, Song 2015, Thompson 2012). The variant was also identified in the following databases: dbSNP (ID: rs149331537) as With Uncertain significance allele, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Counsyl, Color Genomics), and LOVD 3.0 (2X). The variant was not identified in the Cosmic or MutDB databases. The variant was identified in control databases in 19 of 277192 chromosomes at a frequency of 0.000069 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24034 chromosomes (freq: 0.00004), Other in 1 of 6466 chromosomes (freq: 0.0002), European Non-Finnish in 16 of 126684 chromosomes (freq: 0.0001), European Finnish in 1 of 25790 chromosomes (freq: 0.00004), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Leu262 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Leu262Val variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In addition, Human Splicing Finder (HSF) splice analysis showed the possible introduction of a cryptic donor site caused by c.784T>G (Thompson 2012). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.