17-58703332-A-T

Variant names:

• chr17-58703332-A-T
• rs878855179
• NM_058216.3:c.705+3A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_058216.3(RAD51C):​c.705+3A>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000000686 in 1,458,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAD51C NM_058216.3 splice_region, intron
• Scores: Splicing: ADA: 0.9986
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.45
• Publications: 3 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):

• breast-ovarian cancer, familial, susceptibility to, 3

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

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	NM_058216.3	MANE Select	c.705+3A>T		splice_region intron	N/A	NP_478123.1
	RAD51C	NR_103872.2		n.580+3A>T		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.705+3A>T		splice_region intron	N/A	ENSP00000336701.4
	RAD51C	ENST00000482007.5	TSL:1	n.*133+3A>T		splice_region intron	N/A	ENSP00000433332.1
	RAD51C	ENST00000697677.1		n.1789A>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458712 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725830

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109618

Other (OTH) AF: 0.00 AC: 0 AN: 60316

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Feb 18, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.705+3A>T intronic variant results from an A to T substitution 3 nucleotides after coding exon 4 in the RAD51C gene. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Based on the available evidence, the clinical significance of this variant remains unclear.

Fanconi anemia complementation group O Uncertain:1

Nov 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 4 of the RAD51C gene. It does not directly change the encoded amino acid sequence of the RAD51C protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 471450). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.97
PhyloP100		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.32		Position offset: -3

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

Other links and lift over

dbSNP: rs878855179; hg19: chr17-56780693;