chr17-58732547-CAGT-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000691214: 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)." and additional evidence is available in ClinVar.

• 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:25
• 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):

• 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

LOC105371843 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000691214: 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).; SCV006052440: 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).; SCV000255311: 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).; SCV000150079: published functional studies demonstrate a damaging effect on splicing (PMID: 24139550, 27616075, 33333735); SCV004220129: 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)).; SCV000886446: 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).; SCV004017748: Functional studies indicate this variant impacts protein function [PMID: 24139550, 26057125].
• 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.

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.1026+5_1026+7delGTA		splice_region intron	N/A	NP_478123.1	O43502-1
	RAD51C	NR_103872.2		n.901+5_901+7delGTA		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.1026+5_1026+7delGTA		splice_region intron	N/A	ENSP00000336701.4	O43502-1
	RAD51C	ENST00000482007.5	TSL:1	n.*454+5_*454+7delGTA		splice_region intron	N/A	ENSP00000433332.1	Q7KZJ0
	RAD51C	ENST00000583539.5	TSL:2	c.1031_1033delGTA	p.Ser344del	disruptive_inframe_deletion	Exon 8 of 8	ENSP00000463121.1	J3QKK3

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Breast-ovarian cancer, familial, susceptibility to, 3 (7)
5	-	-	not provided (5)
4	-	-	Hereditary cancer-predisposing syndrome (4)
2	-	-	Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 (2)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Fanconi anemia complementation group O (1)
1	-	-	Hereditary cancer (1)
1	-	-	Hereditary site-specific ovarian cancer syndrome (1)
1	-	-	Uterine corpus cancer (1)

Computational scores

Source: dbNSFP v4.9

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;