17-58732547-CAGT-C

Position:

• chr17-58732547-CAGT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. 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:20
• Conservation: PhyloP100: 5.25

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant 17-58732547-CAGT-C is Pathogenic according to our data. Variant chr17-58732547-CAGT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58732547-CAGT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.1026+5_1026+7delGTA		splice_region_variant, intron_variant		ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.1026+5_1026+7delGTA		splice_region_variant, intron_variant		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

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251392 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135864

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: 0.0000264

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

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: 0.00

Gnomad4 NFE exome AF: 0.0000370

Gnomad4 OTH exome AF: 0.0000498

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

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: 0.0000735

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	RAD51C: PS3:Moderate, PS4:Moderate, PM2:Supporting, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 21, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 17, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2024	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, 28905878, 26681312, 33753322, 32957588, 32854451, 31589614, 30374176, 29978187, 35740625, 34371384, 31882575, 30086788, 34923718, 34887416, 30257646, 28888541, 29922827, 36974006, 33333735) -

Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	May 17, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Biologie et Génétique du Cancer, Centre François Baclesse	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 06, 2023	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]. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 06, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 06, 2024	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. -

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 04, 2022	- -

Breast and/or ovarian cancer Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

Hereditary site-specific ovarian cancer syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

King Laboratory, University of Washington

Sep 01, 2019

- -

Hereditary cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Fanconi anemia complementation group O Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

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 introduces a new termination codon (PMID: 24139550, 26057125, 28905878, 31843900; Invitae). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 17, 2022

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. -

Uterine corpus cancer Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Feb 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs587781410; hg19: chr17-56809908;