17-58703201-C-T

Variant names:

• chr17-58703201-C-T
• rs200293302
• NM_058216.3:c.577C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_058216.3(RAD51C):​c.577C>T​(p.Arg193*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,459,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R193R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: RAD51C NM_058216.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23
• Conservation: PhyloP100: 0.319
• Publications: 27 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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-58703201-C-T is Pathogenic according to our data. Variant chr17-58703201-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 140849.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.577C>T	p.Arg193*	stop_gained	Exon 4 of 9	NP_478123.1	O43502-1
	RAD51C	NR_103872.2		n.452C>T		non_coding_transcript_exon	Exon 3 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.577C>T	p.Arg193*	stop_gained	Exon 4 of 9	ENSP00000336701.4	O43502-1
	RAD51C	ENST00000482007.5	TSL:1	n.*5C>T		non_coding_transcript_exon	Exon 3 of 8	ENSP00000433332.1	Q7KZJ0
	RAD51C	ENST00000482007.5	TSL:1	n.*5C>T		3_prime_UTR	Exon 3 of 8	ENSP00000433332.1	Q7KZJ0

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251204 AF XY: 0.0000516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000459 AC: 67 AN: 1459502 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34 AN XY: 726236

African (AFR) AF: 0.0000299 AC: 1 AN: 33410

American (AMR) AF: 0.000112 AC: 5 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000531 AC: 59 AN: 1110118

Other (OTH) AF: 0.0000166 AC: 1 AN: 60316

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000541 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Breast-ovarian cancer, familial, susceptibility to, 3 (5)
5	-	-	Hereditary cancer-predisposing syndrome (5)
4	-	-	not provided (4)
3	-	-	Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 (3)
2	-	-	RAD51C-related disorder (2)
1	-	-	Breast carcinoma (1)
1	-	-	Fanconi anemia complementation group O (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Inherited ovarian cancer (without breast cancer) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.15	N
PhyloP100		0.32
Vest4		0.72
ClinPred		0.53	D
GERP RS		3.8
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200293302; hg19: chr17-56780562;