17-58709857-A-G

Variant names:

• chr17-58709857-A-G
• rs587780259
• NM_058216.3:c.706-2A>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_058216.3(RAD51C):​c.706-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000299 in 1,602,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: RAD51C NM_058216.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24
• Conservation: PhyloP100: 6.97

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11671088 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.2, offset of 10, new splice context is: ctgtatttgggttcgactAGtga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 17-58709857-A-G is Pathogenic according to our data. Variant chr17-58709857-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58709857-A-G is described in Lovd as [Likely_pathogenic]. Variant chr17-58709857-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.706-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 8	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.706-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 8	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151984 Hom.: 0 Cov.: 30

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251368 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135850

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000310 AC: 45 AN: 1450912 Hom.: 0 Cov.: 30 AF XY: 0.0000374 AC XY: 27 AN XY: 722504

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000381

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151984 Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2 AN XY: 74218

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000593 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:24

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Nov 02, 2014

Leiden Open Variation Database

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. -

Aug 06, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant demonstrated to result in an in-frame loss of the adjacent exon (PMID: 35740625) in a gene for which loss of function is a known mechanism of disease; Observed in individuals with breast and ovarian cancer as well as an individual with a chordoma (PMID: 22006311, 22538716, 24139550, 25452441, 26261251, 29255180, 29053726, 28123851, 28888541, 30441849, 30949688, 34326862, 29522266, 36495689, 38700789); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25470109, 24240112, 28123851, 29053726, 29143133, 30949688, 24315737, 22006311, 22538716, 24139550, 24549055, 25452441, 26261251, 26681312, 26720728, 29255180, 28152038, 28776603, 28905878, 31173646, 30441849, 30322717, 31589614, 33333735, 29961768, 32107557, 32359370, 20400964, 22167183, 26354865, 21990120, 20400963, 35740625, 14704354, 34326862, 29922827, 28888541, 29522266, 36495689, 38700789) -

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

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RAD51C: PVS1, PS3:Supporting, PS4:Supporting -

Nov 20, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:6

Dec 09, 2022

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1, PS3, PS4_STR, PP1 -

Jan 15, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratoire de Biologie et Génétique du Cancer, Centre François Baclesse

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RAD51C c.706-2A>G variant was identified in 12 of 15014 proband chromosomes (frequency: 0.0008) from individuals or families with breast and ovarian cancer (Castera 2014, Couch 2015, Golmard 2013, Loveday 2012, Song 2015). The variant was also identified in the following databases: dbSNP (ID: rs587780259) as "With Pathogenic allele", ClinVar (5x pathogenic, 2x likely pathogenic), Clinvitae, and LOVD 3.0 (1x). The variant was not identified in Cosmic or the MutDB database. The variant was identified in control databases in 6 of 277092 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the European population in 6 of 126600 chromosomes (freq: 0.00005), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. Functional studies utilizing mRNA from lymphoblastoid cell lines shows this variant affects splicing, resulting in in-frame skipping of exon 5 (Golmard 2013, Davy 2017). The c.706-2A>G variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 pathogenic. -

Fanconi anemia complementation group O Pathogenic:4

Jun 13, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 4 of the RAD51C gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs587780259, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 22006311, 22538716, 24549055, 25452441, 26261251, 26681312, 29255180). ClinVar contains an entry for this variant (Variation ID: 128209). Studies have shown that disruption of this splice site results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (PMID: 22006311, 24139550; internal data). This variant disrupts a region of the RAD51C protein in which other variant(s) (p.Arg258His) have been determined to be pathogenic (PMID: 20400963, 22167183, 26354865). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jul 22, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Aug 16, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Jan 25, 2022

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 29, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.706-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 5 of the RAD51C gene. This alteration has been reported in multiple individuals with personal and/or family history of breast and/or ovarian cancer (Meindl A et al. Nat. Genet. 2010 May;42:410-4; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Loveday C et al. Nat. Genet. 2012 May;44:475-6; Golmard L et al. BMC Cancer. 2013 Oct;13:484; Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22:1305-13; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32; Kotoula V et al. Am J Cancer Res. 2017 Jan;7:98-114; Harter P et al. PLoS ONE. 2017 Oct;12:e0186043; Golmard L et al. Eur. J. Hum. Genet. 2017 12;25:1345-1353). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA analyses have shown that this mutation leads to skipping of exon 5, resulting in an in-frame deletion of 44 amino acid residues including the Walker B box in the functionally important RecA domain (Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Golmard L et al. BMC Cancer. 2013 Oct;13:484; Davy G et al. Eur. J. Hum. Genet. 2017 10;25:1147-1154; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Feb 18, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an A to G nucleotide substitution at the -2 position of intron 4 of the RAD51C gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies have shown that this variant causes the skipping of exon 5, resulting in an in-frame deletion of 44 amino acids including the Walker B motif in the ATP-binding domain of the RAD51C protein (PMID: 22006311, 24139550, 28905878, 33333735). This variant is expected to cause a defect in RAD51C protein function. This variant has been reported in many individuals affected with breast or ovarian cancer (PMID: 22006311, 22538716, 24139550, 25452441, 26261251, 26681312, 29053726, 29255180). This variant has been identified in 6/282746 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. -

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RAD51C-related disorder Pathogenic:1

May 17, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RAD51C c.706-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in an individual with peritoneal carcinoma, an individual with squamous cell carcinoma of the head and neck, an individual with pancreatic cancer, individuals with breast and/or ovarian cancer, individuals undergoing hereditary cancer genetic testing, (Table S2, Walsh et al. 2011. PubMed ID: 22006311; Table 1, Loveday et al. 2012. PubMed ID: 22538716; Table 2, Scheckenbach et al. 2013. PubMed ID: 24315737; Table S1, Susswein et al. 2015. PubMed ID: 26681312; Table 2, Yurgelun et al. 2018. PubMed ID: 29961768; Table 1, Li et al. 2019. PubMed ID: 30949688;). RT-PCR analysis and minigene assays suggest this variant results in the in-frame skipping of exon 5 (Table 1, Davy et al. 2017. PubMed ID: 28905878; Sanoguera-Miralles et al. 2020. PubMed ID: 33333735). This variant is reported in 0.0046% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-56787218-A-G). It is interpreted as pathogenic and likely pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/128209/). Variants that disrupt the consensus splice acceptor site in RAD51C are expected to be pathogenic. This variant is interpreted as pathogenic. -

Ovarian neoplasm Pathogenic:1

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

May 08, 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.706-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes the canonical 3' splice acceptor site. Experimental evidence demonstrated that this variant affects mRNA splicing leading to the loss of 44 amino acids in a functional domain of the protein by an in-frame exon 5 skipping (Golmard_2013). The variant allele was found at a frequency of 2e-05 in 251368 control chromosomes. c.706-2A>G has been reported in the literature in multiple individuals affected with Breast and Ovarian Cancer (example, Couch_2015, Golmard_2013). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with complete concordance as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.94	D
GERP RS		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.54		Position offset: 12
DS_AL_spliceai		1.0		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780259; hg19: chr17-56787218;