17-58692789-G-T

Position:

• chr17-58692789-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_058216.3(RAD51C):​c.145+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,854 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAD51C NM_058216.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.54

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 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-58692789-G-T is Pathogenic according to our data. Variant chr17-58692789-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 233766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58692789-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.145+1G>T		splice_donor_variant		ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.145+1G>T		splice_donor_variant		1	NM_058216.3	ENSP00000336701	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727236

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Nov 02, 2014	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2023	Canonical splice site variant shown to result in aberrant splicing and a nonfunctional transcript in a gene for which loss of function is a known mechanism of disease (Meindl et al., 2010); Observed in individuals with RAD51C-related cancers (Meindl et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24993905, 21537932, 25470109, 23117857, 32398771, 20400964) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 27, 2020	This variant causes a G to T nucleotide substitution at the +1 position of intron 1 of the RAD51C gene. A RNA study has shown reduced level of the wild-type transcript and increased level of a non-functional transcript that uses an alternative intron 1 splice donor site (PMID:20400964). This variant has been observed in related individuals affected with breast or ovarian cancer (PMID:20400964). This variant has not been identified 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 Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 29, 2021	The c.145+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the RAD51C gene. This mutation was identified in a German breast and ovarian cancer family. RT-PCR analysis of a c.145+1G>T splicing reporter showed complete inactivation of the donor site. In addition, breast tumor tissue from a c.145+1G>T mutation carrier demonstrated loss of the wild-type allele (Meindl A et al. Nat Genet. 2010 May;42(5):410-4). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 13, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 02, 2024	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

Fanconi anemia complementation group O Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 28, 2023

This sequence change affects a donor splice site in intron 1 of the RAD51C gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 20400964). ClinVar contains an entry for this variant (Variation ID: 233766). Studies have shown disruption of this splice site is associated with increased skipping of partial exon 1, introducing a premature termination codon, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 20400964, 32398771; Invitae). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.79		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs757128712; hg19: chr17-56770150;