rs587781410

Variant names:

• chr17-58732547-CAGT-C
• rs587781410
• NM_058216.3:c.1026+5_1026+7delGTA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_058216.3(RAD51C):​c.1026+5_1026+7delGTA variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000304 in 1,610,152 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: RAD51C NM_058216.3 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24
• Conservation: PhyloP100: 5.25
• Publications: 10 publications found

Genes affected

RAD51C (HGNC:9820): (RAD51 paralog C) This gene is a member of the RAD51 family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51 and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Mutations in this gene are associated with Fanconi anemia-like syndrome. This gene is one of four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

RAD51C Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fanconi anemia complementation group O

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LOC105371843 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-58732547-CAGT-C is Pathogenic according to our data. Variant chr17-58732547-CAGT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 128201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.1026+5_1026+7delGTA		splice_region_variant, intron_variant	Intron 8 of 8	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.1026+5_1026+7delGTA		splice_region_variant, intron_variant	Intron 8 of 8	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251392 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000302 AC: 44 AN: 1458080 Hom.: 0 AF XY: 0.0000234 AC XY: 17 AN XY: 725632

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000370 AC: 41 AN: 1108716

Other (OTH) AF: 0.0000498 AC: 3 AN: 60266

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

African (AFR) AF: 0.00 AC: 0 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:24

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:7

Mar 17, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 26, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 27, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4_MOD,PM2_SUP -

Apr 06, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 24139550, 26057125]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. -

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Laboratoire de Biologie et Génétique du Cancer, Centre François Baclesse

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 17, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The RAD51C variant designated as NM_058216.2:c.1026+5_1026+7delGTA was previously classified as a variant of uncertain significance and is now classified as likely pathogenic. This variant is a nucleotide deletion that affects a consensus splice site in intron 8 of the RAD51C gene. RNA studies of peripheral blood from individuals with the variant have demonstrated that the variant leads to skipping of exon 8, resulting in a frameshift and the generation of a premature stop codon in the final exon (Golmard 2013, PMID:241395; Janatova 2015, PMID:26057125). Nonsense-mediated decay is not expected to result from this variant, but it leads to a removal of the nuclear localization signal which can cause cellular mislocalization (French 2003, PMID:12966089). This variant is not listed in population databases. It has been reported in an unaffected control individual and in individuals with breast cancer, ovarian cancer, and uterine cancer in multiple studies (Loveday 2012, PMID:22538716; Golmard 2013, PMID:2413955; Janatova 2015, PMID:26057125; Kraus 2017, PMID:27616075). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 98% probability of pathogenicity based largely on splice prediction and functional studies, which are consistent with a classification of likely pathogenic. This variant is predicted to alter RAD51C function and modify risk for cancer. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Nov 11, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM2 -

not provided Pathogenic:5

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RAD51C: PS3:Moderate, PS4:Moderate, PM2:Supporting, PP3 -

Oct 17, 2016

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 03, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and published functional studies demonstrate a damaging effect on splicing (PMID: 24139550, 27616075, 33333735); Observed in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 26057125, 22538716, 24139550, 27616075, 32957588, 32854451, 30374176); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24139550, 27616075, 22538716, 26057125, 25470109, 27621404, 12966089, 26681312, 33753322, 32957588, 32854451, 31589614, 30374176, 29978187, 35740625, 34371384, 31882575, 30086788, 34923718, 33047316, 34887416, 30257646, 28888541, 29922827, 36974006, 33333735, 28905878, 40225916) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RAD51C c.1026+5_1026+7del variant has been reported in the published literature in several individuals affected with breast and/or ovarian cancer (PMIDs: 22538716 (2012), 24139550 (2013), 26057125 (2015), 26681312 (2015), 27616075 (2016), 29255180 (2017), 30086788 (2018), 30257646 (2018), 31882575 (2019), 32854451 (2020)). Functional studies have shown that this variant causes aberrant splicing including exon 8 skipping (PMIDs: 24139550 (2013), 26057125 (2015), 27616075 (2016), 28905878 (2017), 31843900 (2019)). The frequency of this variant in the general population, 0.000026 (3/113684 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:4

Sep 06, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1026+5_1026+7delGTA intronic variant results from a deletion of 3 nucleotides from the +5 to +7 positions after coding exon 8 in the RAD51C gene. This alteration has been identified in high-risk breast and ovarian cancer families (Loveday C et al. Nat. Genet. 2012 May;44:475-6; Golmard L et al. BMC Cancer. 2013 Oct;13:484; Janatova M et al. PLoS One. 2015 Jun;10:e0127711; Susswein LR et al. Genet Med, 2016 08;18:823-32; Golmard L et al. Eur J Hum Genet, 2017 12;25:1345-1353; Penkert J et al. Breast Cancer Res, 2018 08;20:87; Hoyer J et al. BMC Cancer, 2018 Sep;18:926; Jarhelle E et al. Sci Rep, 2019 12;9:19986; Fanale D et al. Cancers (Basel), 2020 Aug;12). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and multiple studies have demonstrated exon 8 skipping associated with this allele (Golmard L et al. BMC Cancer. 2013 Oct;13:484; Janatova M et al. PLoS One. 2015 Jun;10:e0127711; Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec; Sanoguera-Miralles L et al. Cancers (Basel), 2020 Dec;12; Ambry internal data). The deleted region is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Sep 21, 2021

Sema4, Sema4

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 09, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a 3-basepair deletion at the +5 to +7 positions in intron 8 of the RAD51C gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have reported this variant to cause the skipping of exon 8 by RT-PCR of patient derived total RNA, resulting in frameshift and premature translation stop signal (PMID: 24139550, 26057125, 27616075, 28905878, 31843900). This aberrant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein lacking the functionally important nuclear localization signal (a.a. 366-370), which is required for nuclear localization and robust DNA damage response of the RAD51C protein (PMID: 12966089). This variant has been reported in four individuals affected with ovarian cancer (PMID: 24139550, 26057125, 31882575, 32957588), at least five individuals affected with breast cancer (PMID: 22538716, 27616075, 29255180, 30086788, 30257646, 32854451), as well as one individual with renal cell carcinoma (PMID: 29978187). This variant has also been identified in 3/251392 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. -

Dec 17, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1(RNA)_Strong, PM2_Supporting, PP4 The RAD51C c.1026+5_1026+7del intronic variant results from a deletion of 3 nucleotides from the +5 to +7 positions after coding exon 8 in the RAD51C gene. This variant is found in 1/268265 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset (PM2_supporting). The SpliceAI algorithm predicts that the variant impairs the splicing donor site (deltascore: 0.88), that would lead to skipping of exon 8. RNA studies of peripheral blood from individuals with the variant and minigenes have demonstrated that the variant leads to skipping of exon 8 (r.966_1026del), resulting in a frameshift and the generation of a premature stop codon in the final exon of the gene (p.Arg322Serfs*22). The variant allele does not produce full-lenght transcript (PMID: 24139550, 26057125,28905878, 33333735, 31843900). Nonsense-mediated decay is not expected to result from this variant, but it disrupts the C-terminus of the RAD51C protein, which leads to a removal of the nuclear localization signal that can cause cellular mislocalization (PMID: 12966089) (PVS1(RNA)_Strong). It has been reported in six patients with ovarian cancer (PMID: 26057125, 24139550, 31882575, 32957588, internal data, PP4) and in other patients affected with breast/ovarian cancer or endometrial cancer (PMID: 33333735, 28905878, 31843900, 22538716, 27616075, 30086788, 30374176, 32854451, 34371384, 34923718, internal data). This variant has been reported in ClinVar (6x pathogenic, 14x likely pathogenic) and LOVD (2x pathogenic, 3x likely pathogenic) databases. Based on currently available information, the variant c.1026+5_1026+7del should be considered a likely pathogenic variant. -

Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:2

Aug 06, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary site-specific ovarian cancer syndrome Pathogenic:1

Sep 01, 2019

King Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Breast and/or ovarian cancer Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer Pathogenic:1

Jan 23, 2024

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Mar 17, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RAD51C c.1026+5_1026+7delGTA alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes a 5 prime splicing donor site. Three publications report experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 1.6e-05 in 253704 control chromosomes. c.1026+5_1026+7delGTA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Fanconi anemia complementation group O Pathogenic:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 8 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 likely disrupts the C-terminus of the protein. This variant is present in population databases (rs747311993, gnomAD 0.003%). This variant has been observed in individual(s) with breast cancer, ovarian cancer, kidney cancer, and uterine cancer (PMID: 22538716, 24139550, 26057125, 27616075, 29255180, 29978187, 30086788, 30257646, 30374176, 31882575). ClinVar contains an entry for this variant (Variation ID: 128201). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 8 skipping and retention of intron 8 and introduces a new termination codon (PMID: 24139550, 26057125, 28905878, 31843900; internal data). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts the C-terminus of the RAD51C protein, which contains a signal required for nuclear localization (PMID:12966089). While functional studies have not been performed to directly test the effect of this variant on RAD51C protein function, this suggests that disruption of this region of the protein is causative of disease. 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. -

Uterine corpus cancer Pathogenic:1

Feb 21, 2023

CZECANCA consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.88		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587781410; hg19: chr17-56809908;