17-58709857-A-G

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Strong PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000186640: 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" and additional evidence is available in ClinVar.

• 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:28
• Conservation: PhyloP100: 6.97
• Publications: 16 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):

• RAD51C-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 3

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

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 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.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000186640: 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).; SCV000686377: 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).; SCV001549328: 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).; SCV001363654: 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).; SCV007097381: Classified as Pathogenic following ACMG/AMP guidelines (PVS1, PM2, PS3_supporting). PMID:24549055; SCV004107440: 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).
• PP5: Variant 17-58709857-A-G is Pathogenic according to our data. Variant chr17-58709857-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 128209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058216.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	NM_058216.3	MANE Select	c.706-2A>G		splice_acceptor intron	N/A	NP_478123.1	O43502-1
	RAD51C	NR_103872.2		n.581-2A>G		splice_acceptor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.706-2A>G		splice_acceptor intron	N/A	ENSP00000336701.4	O43502-1
	RAD51C	ENST00000482007.5	TSL:1	n.*134-2A>G		splice_acceptor intron	N/A	ENSP00000433332.1	Q7KZJ0
	RAD51C	ENST00000930423.1		c.706-2A>G		splice_acceptor intron	N/A	ENSP00000600482.1

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

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251368 AF XY: 0.0000221

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: 0.0000440

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

African (AFR) AF: 0.00 AC: 0 AN: 33222

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 86040

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000381 AC: 42 AN: 1102150

Other (OTH) AF: 0.0000333 AC: 2 AN: 60012

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

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000342 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
6	-	-	Breast-ovarian cancer, familial, susceptibility to, 3 (6)
4	-	-	Fanconi anemia complementation group O (4)
3	-	-	Hereditary cancer-predisposing syndrome (3)
2	-	-	Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 (2)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
1	-	-	Familial ovarian cancer (1)
1	-	-	Long QT syndrome (1)
1	-	-	Ovarian neoplasm (1)
1	-	-	RAD51C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.0
GERP RS		6.0
PromoterAI		0.013	Neutral
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587780259; hg19: chr17-56787218; COSMIC: COSV109432295;