chr17-58724105-G-A

Variant names:

• chr17-58724105-G-A
• rs774586107
• NM_058216.3:c.965+5G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_058216.3(RAD51C):​c.965+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000137 in 1,456,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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: "SCV000550196: Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID:22725699, 33011440, 33333735).; SCV000663788: Functional RNA studies have demonstrated that this alteration results in out-of-frame exon skipping and premature protein truncation (Coulet F et al. Clin. Genet. 2013 Apr;83:332-6; Sanoguera-Miralles L et al. Cancers (Basel), 2020 Dec;12; Ambry internal data).; SCV000686408: RNA studies using RT-PCR analysis of a patient sample and mini-gene assays have shown that this variant causes out-of-frame skipping of exon 7 (PMID:22725699, 33011440, 33333735), which is expected to create a frameshift and premature translation stop signal resulting in an absent or non-functional protein product.; SCV005896248: Functional studies indicate this variant impacts protein function [PMID:37444530, 33011440, 22725699, 39299233].".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RAD51C NM_058216.3 splice_region, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.47
• Publications: 4 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000550196: Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22725699, 33011440, 33333735).; SCV000663788: Functional RNA studies have demonstrated that this alteration results in out-of-frame exon skipping and premature protein truncation (Coulet F et al. Clin. Genet. 2013 Apr;83:332-6; Sanoguera-Miralles L et al. Cancers (Basel), 2020 Dec;12; Ambry internal data).; SCV000686408: RNA studies using RT-PCR analysis of a patient sample and mini-gene assays have shown that this variant causes out-of-frame skipping of exon 7 (PMID: 22725699, 33011440, 33333735), which is expected to create a frameshift and premature translation stop signal resulting in an absent or non-functional protein product.; SCV005896248: Functional studies indicate this variant impacts protein function [PMID: 37444530, 33011440, 22725699, 39299233].
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-58724105-G-A is Pathogenic according to our data. Variant chr17-58724105-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 409841.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.965+5G>A		splice_region intron	N/A	NP_478123.1	O43502-1
	RAD51C	NR_103872.2		n.840+5G>A		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.965+5G>A		splice_region intron	N/A	ENSP00000336701.4	O43502-1
	RAD51C	ENST00000482007.5	TSL:1	n.*393+5G>A		splice_region intron	N/A	ENSP00000433332.1	Q7KZJ0
	RAD51C	ENST00000930423.1		c.1067+5G>A		splice_region intron	N/A	ENSP00000600482.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251118 AF XY: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456128 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724664

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106878

Other (OTH) AF: 0.00 AC: 0 AN: 60208

GnomAD4 genome Cov.: 32

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
2	-	-	Breast-ovarian cancer, familial, susceptibility to, 3 (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Fanconi anemia complementation group O (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.80
PhyloP100		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
Splicevardb		3.0
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.92		Position offset: -5

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

Other links and lift over

dbSNP: rs774586107; hg19: chr17-56801466;