NM_058216.3(RAD51C):c.577C>T (p.Arg193Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jul 19, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000129056.16

Allele description [Variation Report for NM_058216.3(RAD51C):c.577C>T (p.Arg193Ter)]

NM_058216.3(RAD51C):c.577C>T (p.Arg193Ter)

Gene:

RAD51C:RAD51 paralog C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q22

Genomic location:

Preferred name:

NM_058216.3(RAD51C):c.577C>T (p.Arg193Ter)

Other names:

p.R193*:CGA>TGA

HGVS:

NC_000017.11:g.58703201C>T
NG_023199.1:g.15600C>T
NM_058216.3:c.577C>TMANE SELECT
NP_478123.1:p.Arg193Ter
LRG_314t1:c.577C>T
LRG_314:g.15600C>T
NC_000017.10:g.56780562C>T
NM_058216.1:c.577C>T
NM_058216.2:c.577C>T
NR_103872.2:n.452C>T
p.R193*

Protein change:

R193*

Links:

dbSNP: rs200293302

NCBI 1000 Genomes Browser:

rs200293302

Molecular consequence:

NR_103872.2:n.452C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_058216.3:c.577C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000183755	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 3, 2021)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 22538716, 22725699, 23117857, 24240112, 25086635, 25470109, 26261251, 26681312, 26689913, 26740214, 26976419, 28588062, 30847381, 30949688, 32658311, 33077847, 33471991 Citation Link,
SCV000292164	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 19, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 22538716, 22725699, 25086635, 26261251, 26740214, 26976419, 30949688, 32658311, 33471991, 25741868
SCV002531829	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Nov 6, 2021)	germline	curation	PubMed (7) [See all records that cite these PMIDs] 22538716, 23117857, 25086635, 26689913, 26740214, 33471991, 20400964 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000183755

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 3, 2021)

germline

clinical testing

PubMed (17)
[See all records that cite these PMIDs]

Citation Link,

SCV000292164

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 19, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV002531829

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Nov 6, 2021)

germline

curation

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.

Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, Thornton A, Norquist BM, Casadei S, Nord AS, Agnew KJ, Pritchard CC, Scroggins S, Garcia RL, King MC, Swisher EM.

Clin Cancer Res. 2014 Feb 1;20(3):764-75. doi: 10.1158/1078-0432.CCR-13-2287. Epub 2013 Nov 15.

PubMed [citation]

PMID:: 24240112
PMCID:: PMC3944197

Genetic testing for RAD51C mutations: in the clinic and community.

Sopik V, Akbari MR, Narod SA.

Clin Genet. 2015 Oct;88(4):303-12. doi: 10.1111/cge.12548. Epub 2015 Jan 7. Review.

PubMed [citation]

PMID:: 25470109

See all PubMed Citations (19)

Details of each submission

From Ambry Genetics, SCV000183755.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000292164.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002531829.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (7)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine