NM_058216.3:c.577C>T

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). 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:20
• Conservation: PhyloP100: 0.319

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 140849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58703201-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.577C>T	p.Arg193*	stop_gained	Exon 4 of 9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.577C>T	p.Arg193*	stop_gained	Exon 4 of 9	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251204 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135786

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000407 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

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Sep 14, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant causes the premature termination of RAD51C protein synthesis. In addition, it has been reported in individuals/families with breast and/or ovarian cancer in the published literature (PMID: 32658311 (2021), 26976419 (2016), 26740214 (2016), 25086635 (2014), 22725699 (2013), 22538716 (2012)). Based on the available information, this variant is classified as pathogenic. -

Aug 03, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22538716, 26740214, 25086635, 26261251, 23117857, 28588062, 22725699, 26720728, 25470109, 26681312, 26976419, 29093764, 29409816, 26689913, 32658311, 31589614, 28888541, 29922827, 34026625, 33077847, 33804961, 33999380, 35626031, 34308104, 33047316, 34326862, 36493725, 36920765, 36169650, 35988656, 36495689, 34887416, 36113475) -

Hereditary cancer-predisposing syndrome Pathogenic:4

Jul 19, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 4 of the RAD51C gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in individuals affected with ovarian cancer (PMID: 22538716, 22725699, 26261251) and breast cancer (PMID: 25086635, 26740214, 26976419, 30949688, 32658311, 33471991). This variant has been identified in 10/251204 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Dec 03, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R193* pathogenic mutation (also known as c.577C>T), located in coding exon 4 of the RAD51C gene, results from a C to T substitution at nucleotide position 577. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been reported in multiple families of different ethnicities with breast and/or ovarian cancer (Loveday C et al. Nat. Genet., 2012 Apr;44:475-6; author reply 476; Kushnir A et al. Breast Cancer Res Treat, 2012 Dec;136:869-74; Coulet F et al. Clin. Genet., 2013 Apr;83:332-6; Pennington KP et al. Clin Cancer Res, 2014 Feb;20:764-75; Blanco A et al. Breast Cancer Res Treat, 2014 Aug;147:133-43; Sopik V et al. Clin Genet, 2015 Oct;88:303-12; Song H et al. J Clin Oncol, 2015 Sep;33:2901-7; Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Jønson L et al. Breast Cancer Res Treat, 2016 Jan;155:215-22; Susswein LR et al. Genet Med, 2016 08;18:823-32; Tung N et al. J Clin Oncol, 2016 May;34:1460-8; Li N et al. J Natl Cancer Inst, 2019 12;111:1332-1338; Akcay IM et al. Int J Cancer, 2021 01;148:285-295; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in a patient with cutaneous melanoma and in an individual with multifocal paragangliomas and B-cell lymphocytosis with a family history of ovarian and colon cancer (Goyal A et al. JAAD Case Rep, 2019 Mar;5:240-241; Aoude LG et al. Sci Rep, 2020 10;10(1):17687). This alteration was shown to be susceptible to PARP inhibitors in mice, demonstrating loss of homologous repair pathway function (Kondrashova O et al. Cancer Discov, 2017 09;7:984-998). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Nov 06, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 04, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PS4_SUP -

Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:4

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 24, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Feb 01, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RAD51C-related disorder Pathogenic:2

Mar 19, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant found in exon 4 of 9 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in RAD51C is an established mechanism of disease (PMID: 30949688, 20400964, 21990120, 24800917). This variant has been previously reported as a heterozygous change in individuals with RAD51C-related disorders (PMID: 22538716, 26740214, 35988656, 36493725, 22725699, 25086635, 26261251). A synonymous change at the same residue (p.Arg193=) has been previously reported in individuals with breast cancer, ovarian cancer, and skin cutaneous melanoma (PMID: 36451132). The c.577C>T (p.Arg193Ter) variant is present in the heterozygous state in the gnomAD v4 population database at a frequency of 0.005% (67/1459502), and is absent in the homozygous state. Based on the available evidence, c.577C>T (p.Arg193Ter) is classified as Pathogenic. -

Apr 05, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RAD51C c.577C>T (p.Arg193Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg193Ter variant has been reported in at least five studies in which it is found in a heterozygous state in seven individuals diagnosed with ovarian cancer, two of whom are related (Loveday et al. 2012; Coulet et al. 2013; Blanco et al. 2014; Song et al. 2015; Jonson et al. 2016). The p.Arg193Ter variant was also reported in a heterozygous state in two unaffected individuals who may yet be too young to develop disease (one individual was 25 years old and the other is of unknown age). All of these individuals have a family history of breast and/or ovarian cancer and are negative for variants in the BRCA1 and BRCA2 genes. The p.Arg193Ter variant was absent from 3,928 controls and is reported at a frequency of 0.00012 in the Latino population of the Genome Aggregation Database. Although the p.Arg193Ter variant has not been reported in the literature in individuals with Fanconi anemia, it cannot be ruled out of causing this condition based on allele frequency in consideration of disease penetrance and prevalence estimates. Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg193Ter variant is classified as pathogenic for RAD51C-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Inherited ovarian cancer (without breast cancer) Pathogenic:1

Jul 01, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1,PM5_Supporting -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Jul 14, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The RAD51C c.577C>T (p.Arg193X) variant results in a premature termination codon, predicted to cause a truncated or absent RAD51C protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/120882 control chromosomes at a frequency of 0.0000414, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). Multiple publications have cited the variant in affected individuals, including a family that the variant cosegregated with disease (Blanco_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Fanconi anemia complementation group O Pathogenic:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg193*) in the RAD51C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917, 29278735). This variant is present in population databases (rs200293302, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 22538716, 22725699, 25086635, 26261251, 26740214). ClinVar contains an entry for this variant (Variation ID: 140849). For these reasons, this variant has been classified as Pathogenic. -

Breast carcinoma Pathogenic:1

Aug 08, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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
Vest4		0.72, 0.72
ClinPred		0.53	D
GERP RS		3.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs200293302; hg19: chr17-56780562;