rs587781995

Positions:

• chr17-58724037-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_058216.3(RAD51C):​c.905-2_905-1delAG variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000683 in 1,611,156 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: RAD51C NM_058216.3 splice_acceptor, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 U:1
• Conservation: PhyloP100: 5.47

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 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 17-58724037-CAG-C is Pathogenic according to our data. Variant chr17-58724037-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58724037-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.905-2_905-1delAG		splice_acceptor_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.905-2_905-1delAG		splice_acceptor_variant, intron_variant		1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152102 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251328 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459054 Hom.: 0 AF XY: 0.00000826 AC XY: 6 AN XY: 726050

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000721

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74298

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 07, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Sep 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The RAD51C c.905-2_905-1delAG variant has been reported in individuals with ovarian cancer (PMID: 26822949; 26261251). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 04, 2023	- -

not provided Pathogenic:4 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2022	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: exon skipping (Lhota 2016); This variant is associated with the following publications: (PMID: 26261251, 28152038, 26822949, 31446535, 29625052, 26689913, 33333735, 30613976) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	RAD51C: PVS1, PM2, PS4:Moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Jul 20, 2019	Curator: Arleen D. Auerbach. Submitter to LOVD: Zdenek Kleibl. -

Breast and/or ovarian cancer Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	CZECANCA consortium	Jun 11, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 18, 2022	- -

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 28, 2024	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 27, 2023	The c.905-2_905-1delAG pathogenic mutation results from the deletion of two nucleotides located before the first nucleotide of coding exon 7 in the RAD51C gene. This alteration has been seen in multiple patients with personal and family histories of breast and ovarian cancer (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Lhota F et al. Clin. Genet. 2016 Oct;90(4):324-33; Li N et al. J. Natl. Cancer Inst. 2019 Apr; Rizzolo et al. Int. J. Cancer. 2019). In a large case control study, the c.905-2_905-1delAG variant was not seen in over 3000 pancreatic cancer patients (Hu C et al. JAMA. 2018 06;319:2401-2409). In another case control study, the c.905-2_905-1delAG variant was found to be statistically associated with breast cancer (OR= 6.9, 95% CI 1.34-35.61, p=0.02) (Sanoguera-Miralles L et al. Cancers (Basel), 2020 Dec;12:). The deleted nucleotide positions are highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA analyses have shown that this alteration results in skipping of exon 7 and the creation of an out of frame transcript (Lhota F et al. Clin. Genet. 2016 Oct;90(4):324-33, Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 06, 2023	This variant deletes the last two nucleotides in intron 6 of the RAD51C gene. This variant is also known as c.905-2delAG and c.905-2_1delAG in the literature. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have shown that this variant results in the skipping of exon 7 (r.905_965del) that is predicted to result in an absent or non-functional protein product (PMID: 26822949, 33333735). This variant has been observed in individuals affected with ovarian cancer, breast cancer, or pancreatic cancer (PMID: 26261251, 26822949, 30333958, 30613976, 33471991, 37065479). This variant has been identified in 3/251328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Fanconi anemia complementation group O Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2024

This sequence change affects a splice site in intron 6 of the RAD51C gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs587781995, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with ovarian cancer and breast cancer (PMID: 26261251, 26822949). This variant is also known as 905-2delAG and c.905-2_1delAG. ClinVar contains an entry for this variant (Variation ID: 141768). Studies have shown that disruption of this splice site results in skipping of exon 7 and introduces a new termination codon (internal data). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts the nuclear localization signal (NLS) of the RAD51C protein, which is important for proper localization and function of the RAD51C protein (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. For these reasons, this variant has been classified as 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

Jun 09, 2022

Variant summary: RAD51C c.905-2_905-1delAG 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: Four predict the variant abolishes a 3' acceptor site. This has been confirmed via cDNA sequencing (Lhota_2016) and a minigene splicing assay (Sanoguera-Miralles_2020). The variant allele was found at a frequency of 1.2e-05 in 251328 control chromosomes (gnomAD). c.905-2_905-1delAG has been reported in the literature in multiple individuals affected with Breast and Ovarian Cancer (e.g. Song_2015, Lu_2015, Lhota_2016, Rizzolo_2019, Cerretini_2019, Dorling_2021). These data indicate that the variant is likely to be associated with disease. Nine ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance, four as likely pathogenic, and four as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.91		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: rs587781995; hg19: chr17-56801398;