rs587780835

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The ENST00000337432.9(RAD51C):​c.1027-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000137 in 1,459,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RAD51C
ENST00000337432.9 splice_acceptor

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3

Conservation

PhyloP100: 3.58
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 1.3200707 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of 6, new splice context is: tttttatctttcggcctcAGgga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAD51CNM_058216.3 linkuse as main transcriptc.1027-2A>G splice_acceptor_variant ENST00000337432.9 NP_478123.1
LOC105371843XR_007065866.1 linkuse as main transcriptn.81-9691T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAD51CENST00000337432.9 linkuse as main transcriptc.1027-2A>G splice_acceptor_variant 1 NM_058216.3 ENSP00000336701 P2O43502-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459690
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
725912
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria providedresearchLaboratory for Genotyping Development, RIKENJul 01, 2021- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 11, 2023Variant summary: RAD51C c.1027-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. Four predict the variant creates a cryptic 3 acceptor site and results in an in-frame deletion of two amino acids. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.8e-06 in 294720 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1027-2A>G has been reported in the literature in at least one individual affected with Hereditary Breast And Ovarian Cancer Syndrome, as well as in controls (Desmond_2015, Mizukami_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26270727, 35806449, 32980694). Three ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 05, 2023The c.1027-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 9 in the RAD51C gene. This alteration has been observed in the literature in one patient with ovarian cancer (Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of two amino acids; however, the exact functional impact of the deleted amino acids are unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 04, 2023In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 9 (Invitae). ClinVar contains an entry for this variant (Variation ID: 136155). Disruption of this splice site has been observed in individual(s) with personal and family history of breast and/or ovarian cancer (PMID: 26270727). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 8 of the RAD51C gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 2 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
34
DANN
Uncertain
0.98
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.86
D
MutationTaster
Benign
1.0
D
GERP RS
4.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.88
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.49
Position offset: 8
DS_AL_spliceai
0.88
Position offset: 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.

Other links and lift over

dbSNP: rs587780835; hg19: chr17-56811477; API