Submissions for variant NM_058216.3(RAD51C):c.904+5G>T

gnomAD frequency: 0.00001  dbSNP: rs587782702

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132144	SCV000187215	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	The c.904+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 6 in the RAD51C gene. This variant was reported in a hereditary breast and ovarian cancer (HBOC) kindred and segregated with both ovarian and early-onset breast cancer in this family. In the tested affected individuals, c.904+5G>T was associated with somatic loss of heterozygosity (LOH) in 2/2 analyzed tumors (1 breast and 1 ovarian) (Meindl A et al. Nat. Genet. 2010 May;42(5):410-4). This alteration has been identified in an individual diagnosed with ovarian cancer (Loveday C et al. Nat. Genet. 2012 May;44(5):475-6) and in multiple individuals diagnosed with breast cancer (Fostira F et al. J. Med. Genet., 2020 01;57:53-61). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA analyses have identified skipping of exon 6 in individuals with this alteration (Meindl A et al. Nat. Genet. 2010 May;42(5):410-4, Casadei S et al. Proc. Natl. Acad. Sci. U.S.A., 2019 Dec; Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000225845	SCV000291252	pathogenic	Fanconi anemia complementation group O	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change falls in intron 6 of the RAD51C gene. It does not directly change the encoded amino acid sequence of the RAD51C protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587782702, gnomAD 0.004%). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 20400964, 22538716, 24993905, 31300551, 32885271). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142762). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20400964, 31843900; Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000484863	SCV000566207	likely pathogenic	not provided	2021-09-24	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and both in silico predictors and evolutionary conservation support a deleterious effect; Observed in individuals with a personal history of breast and/or ovarian cancer as well as other cancers (Meindl 2010, Loveday 2012, Waszak 2018, Tsaousis 2019, Guglielmi 2021); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24993905, 23117857, 25470109, 25525159, 22538716, 20400964, 29753700, 31159747, 31300551, 31843900, 32359370, 30949688, 31589614, 32885271, 34299313)
Color Diagnostics, LLC DBA Color Health	RCV000132144	SCV000691285	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-07	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +5 position of intron 6 of the RAD51C gene. Functional RNA studies have shown that this variant results in abnormal RNA splicing, creating a premature translation stop signal in the RNA transcript (PMID: 20400964, 31843900). The aberrant transcripts are expected to result in an absent or non-functional protein product. This variant has been reported in five individuals affected with ovarian cancer (PMID: 20400964, 22538716, 31300551, 32885271, 34299313) and three individuals affected with familial breast cancer (PMID: 31300551, 34299313). This variant has been identified in 4/250536 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
GeneKor MSA	RCV000484863	SCV000821778	likely pathogenic	not provided	2021-01-09	criteria provided, single submitter	clinical testing	This variant is a substitution of the fifth nucleotide of intron 6 of the RAD51C gene. This location is highly conserved in human and other genomes. It causes incorrect splicing of the mRNA produced by this allele and deletion of the entire exon. Thus, the protein produced is truncated and non functional (PMID: 20400964). The mutation has been described in literature in patients with breast and ovarian cancer (PMID: 22538716, PMID: 20400964). The mutation database ClinVar contains an entry for this variant (Variation ID: 142762).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000484863	SCV001446599	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798459	SCV002043697	likely pathogenic	Breast and/or ovarian cancer	2021-04-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000484863	SCV002545958	likely pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	RAD51C: PM2, PS3:Moderate, PP1, PP3
Baylor Genetics	RCV000007225	SCV004209777	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-10-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484863	SCV004220155	likely pathogenic	not provided	2023-05-22	criteria provided, single submitter	clinical testing	The RAD51C c.904+5G>T variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMID: 32885271 (2021), 31300551 (2020), 24993905 (2014), 22538716 (2012)). A splicing study showed damaging results regarding the variant's impact on normal RAD51C mRNA splicing (PMID: 31843900 (2019)). The frequency of this variant in the general population, 0.000035 (4/113520 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper RAD51C mRNA splicing. Based on the available information, this variant is classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003935224	SCV004764039	likely pathogenic	RAD51C-related condition	2023-12-19	criteria provided, single submitter	clinical testing	The RAD51C c.904+5G>T variant is predicted to interfere with splicing. This variant has been reported in individuals with familial breast/ovarian cancer and in vitro RT-PCR analysis on this variant confirmed the exclusion of exon 6 (Meindl et al. 2010. PubMed ID: 20400964). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as likely pathogenic/pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/142762/). This variant is interpreted as likely pathogenic.
OMIM	RCV000007225	SCV000027421	risk factor	Breast-ovarian cancer, familial, susceptibility to, 3	2010-05-01	no assertion criteria provided	literature only
King Laboratory, University of Washington	RCV001171471	SCV001251383	pathogenic	Hereditary site-specific ovarian cancer syndrome	2019-09-01	no assertion criteria provided	research
Leiden Open Variation Database	RCV000484863	SCV001365280	pathogenic	not provided	2019-12-23	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitters to LOVD: Florentia Fostira, Johan den Dunnen.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000007225	SCV001552481	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3		no assertion criteria provided	clinical testing	The RAD51C c.904+5G>T variant was identified in 3 of 4986 proband chromosomes (frequency: 0.0006) from individuals or families with HBOC and was not identified in 8536 control chromosomes from healthy individuals (Loveday 2012,Meindl 2009 ,Kushnir 2012). The variant was also identified in dbSNP (ID: rs587782702) as "With Likely pathogenic allele", ClinVar (5x Likely Pathogenic by Invitae, Ambry Genetics, GeneDx and two other clinical laboratory, 1x risk factor by OMIM) and LOVD 3.0. The variant was identified in control databases in 4 of 245382 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 4 of 111496 chromosomes (freq: 0.00004), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish and South Asian populations. A functional study demonstrated that RT-PCR analysis of RNA transfected in a mini-gene assay revealed exclusion of exon 6 with the splice donor mutation compared to wild type 5' splice site. In addition, the variant was identified in a family pedigree that demonstrated disease segregation (Meindl 2009). The c.904+5G>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 3 of 3 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as likely pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000484863	SCV002035058	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000484863	SCV002037241	likely pathogenic	not provided		no assertion criteria provided	clinical testing