17-58720817-G-T

Position:

chr17-58720817-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_058216.3(RAD51C):c.904+5G>T variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00000873 in 1,602,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 splice_donor_5th_base, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17O:1

Conservation

PhyloP100: 5.17

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-58720817-G-T is Pathogenic according to our data. Variant chr17-58720817-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58720817-G-T is described in Lovd as [Pathogenic]. Variant chr17-58720817-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3 linkuse as main transcript	c.904+5G>T		splice_donor_5th_base_variant, intron_variant		ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9 linkuse as main transcript	c.904+5G>T		splice_donor_5th_base_variant, intron_variant		1	NM_058216.3	P2	O43502-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250536

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135542

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000827

AC:

AN:

1450692

Hom.:

Cov.:

AF XY:

0.00000969

AC XY:

AN XY:

722444

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000109

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000615

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	RAD51C: PM2, PS3:Moderate, PP1, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 22, 2023	The RAD51C c.904+5G>T variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMID: 32885271 (2021), 31300551 (2020), 24993905 (2014), 22538716 (2012)). A splicing study showed damaging results regarding the variant's impact on normal RAD51C mRNA splicing (PMID: 31843900 (2019)). The frequency of this variant in the general population, 0.000035 (4/113520 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper RAD51C mRNA splicing. Based on the available information, this variant is classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Dec 23, 2019	Curator: Arleen D. Auerbach. Submitters to LOVD: Florentia Fostira, Johan den Dunnen. -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 09, 2021	This variant is a substitution of the fifth nucleotide of intron 6 of the RAD51C gene. This location is highly conserved in human and other genomes. It causes incorrect splicing of the mRNA produced by this allele and deletion of the entire exon. Thus, the protein produced is truncated and non functional (PMID: 20400964). The mutation has been described in literature in patients with breast and ovarian cancer (PMID: 22538716, PMID: 20400964). The mutation database ClinVar contains an entry for this variant (Variation ID: 142762). -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2021	Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and both in silico predictors and evolutionary conservation support a deleterious effect; Observed in individuals with a personal history of breast and/or ovarian cancer as well as other cancers (Meindl 2010, Loveday 2012, Waszak 2018, Tsaousis 2019, Guglielmi 2021); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24993905, 23117857, 25470109, 25525159, 22538716, 20400964, 29753700, 31159747, 31300551, 31843900, 32359370, 30949688, 31589614, 32885271, 34299313) -

Breast-ovarian cancer, familial, susceptibility to, 3

Pathogenic:3Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The RAD51C c.904+5G>T variant was identified in 3 of 4986 proband chromosomes (frequency: 0.0006) from individuals or families with HBOC and was not identified in 8536 control chromosomes from healthy individuals (Loveday 2012,Meindl 2009 ,Kushnir 2012). The variant was also identified in dbSNP (ID: rs587782702) as "With Likely pathogenic allele", ClinVar (5x Likely Pathogenic by Invitae, Ambry Genetics, GeneDx and two other clinical laboratory, 1x risk factor by OMIM) and LOVD 3.0. The variant was identified in control databases in 4 of 245382 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 4 of 111496 chromosomes (freq: 0.00004), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish and South Asian populations. A functional study demonstrated that RT-PCR analysis of RNA transfected in a mini-gene assay revealed exclusion of exon 6 with the splice donor mutation compared to wild type 5' splice site. In addition, the variant was identified in a family pedigree that demonstrated disease segregation (Meindl 2009). The c.904+5G>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 3 of 3 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as likely pathogenic. -
risk factor, no assertion criteria provided	literature only	OMIM	May 01, 2010	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 03, 2024	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 20400964]. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 28, 2023	The c.904+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 6 in the RAD51C gene. This variant was reported in a hereditary breast and ovarian cancer (HBOC) kindred and segregated with both ovarian and early-onset breast cancer in this family. In the tested affected individuals, c.904+5G>T was associated with somatic loss of heterozygosity (LOH) in 2/2 analyzed tumors (1 breast and 1 ovarian) (Meindl A et al. Nat. Genet. 2010 May;42(5):410-4). This alteration has been identified in an individual diagnosed with ovarian cancer (Loveday C et al. Nat. Genet. 2012 May;44(5):475-6) and in multiple individuals diagnosed with breast cancer (Fostira F et al. J. Med. Genet., 2020 01;57:53-61). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA analyses have identified skipping of exon 6 in individuals with this alteration (Meindl A et al. Nat. Genet. 2010 May;42(5):410-4, Casadei S et al. Proc. Natl. Acad. Sci. U.S.A., 2019 Dec; Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 07, 2022	This variant causes a G to T nucleotide substitution at the +5 position of intron 6 of the RAD51C gene. Functional RNA studies have shown that this variant results in abnormal RNA splicing, creating a premature translation stop signal in the RNA transcript (PMID: 20400964, 31843900). The aberrant transcripts are expected to result in an absent or non-functional protein product. This variant has been reported in five individuals affected with ovarian cancer (PMID: 20400964, 22538716, 31300551, 32885271, 34299313) and three individuals affected with familial breast cancer (PMID: 31300551, 34299313). This variant has been identified in 4/250536 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. -

Hereditary site-specific ovarian cancer syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

research

King Laboratory, University of Washington

Sep 01, 2019

- -

Breast and/or ovarian cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 28, 2021

- -

RAD51C-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2023

The RAD51C c.904+5G>T variant is predicted to interfere with splicing. This variant has been reported in individuals with familial breast/ovarian cancer and in vitro RT-PCR analysis on this variant confirmed the exclusion of exon 6 (Meindl et al. 2010. PubMed ID: 20400964). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as likely pathogenic/pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/142762/). This variant is interpreted as likely pathogenic. -

Fanconi anemia complementation group O

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change falls in intron 6 of the RAD51C gene. It does not directly change the encoded amino acid sequence of the RAD51C protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587782702, gnomAD 0.004%). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 20400964, 22538716, 24993905, 31300551, 32885271). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142762). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20400964, 31843900; Invitae). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.94

Position offset: -5

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