chr17-58703325-C-G

Position:

chr17-58703325-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_058216.3(RAD51C):c.701C>G(p.Ser234*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000285 in 1,611,582 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.59

Variant links:

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 links:

RAD51C (HGNC:):

RAD51C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 17-58703325-C-G is Pathogenic according to our data. Variant chr17-58703325-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 142919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58703325-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3 linkuse as main transcript	c.701C>G	p.Ser234*	stop_gained	4/9	ENST00000337432.9	NP_478123.1	O43502-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9 linkuse as main transcript	c.701C>G	p.Ser234*	stop_gained	4/9	1	NM_058216.3	ENSP00000336701.4		O43502-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251104

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135738

show subpopulations

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 SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000295

AC:

AN:

1459472

Hom.:

Cov.:

AF XY:

0.0000496

AC XY:

AN XY:

726220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000487

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 27, 2022	The p.S234* pathogenic mutation (also known as c.701C>G), located in coding exon 4 of the RAD51C gene, results from a C to G substitution at nucleotide position 701. This changes the amino acid from a serine to a stop codon within coding exon 4. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	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 identified in 16/251104 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. -

Breast-ovarian cancer, familial, susceptibility to, 3

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 03, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Skane University Hospital Lund

May 27, 2022

- -

Malignant tumor of breast

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The RAD51C p.Ser234X variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs587782818) as â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹, ClinVar (as pathogenic by Ambry Genetics and Invitae), and Clinvitae (2x as pathogenic) databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ser234X variant leads to a premature stop codon at position 234 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the RAD51C gene are an established mechanism of disease in hereditary breast cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Fanconi anemia complementation group O

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 30, 2023

This sequence change creates a premature translational stop signal (p.Ser234*) 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 (rs587782818, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with clinical features of RAD51C-related conditions (PMID: 32107557). ClinVar contains an entry for this variant (Variation ID: 142919). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Uncertain

0.86

Vest4

0.88, 0.87

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over