chr17-35101205-CG-C

Position:

• chr17-35101205-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000345365.11(RAD51D):​c.898del​(p.Arg300AspfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R300R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51D ENST00000345365.11 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.33

Genes affected

RAD51D (HGNC:9823): (RAD51 paralog D) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene. [provided by RefSeq, Jan 2011]

RAD51L3-RFFL (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-35101205-CG-C is Pathogenic according to our data. Variant chr17-35101205-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4	c.898del	p.Arg300AspfsTer10	frameshift_variant	9/10	ENST00000345365.11	NP_002869.3
RAD51L3-RFFL	NR_037714.1	n.650del		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.898del	p.Arg300AspfsTer10	frameshift_variant	9/10	1	NM_002878.4	ENSP00000338790	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 02, 2021	In summary, this variant is a rare truncation that likely disrupts an important functional domain in the RAD51D protein. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is expected to disrupt amino acid residues Arg300-Thr328 of the RAD51D protein, thereby removing the C-terminus of the ATPase domain (PMID: 14704354, 19327148, 21111057). Although functional studies have not been done for this particular variant, experimental studies using yeast two-hybrid analysis has shown that the region of the RAD51D protein necessary for RAD51C complexing localizes to the last ~100 amino acids (PMID: 10749867, 14704354, 19327148). The data indicates that this variant likely disrupts this important RAD51D-RAD51C interaction. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 185528). This sequence change deletes 1 nucleotide from exon 9 of the RAD51D mRNA (c.898delC), causing a frameshift at codon 300. This creates a premature translational stop signal in the last exon of the RAD51D mRNA (p.Arg300Aspfs*10). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acids of the RAD51D protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 04, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 19, 2023	This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 17, 2024	The c.898delC variant, located in coding exon 9 of the RAD51D gene, results from a deletion of one nucleotide at nucleotide position 898, causing a translational frameshift with a predicted alternate stop codon (p.R300Dfs*10). This variant has been reported in ovarian cancer cohorts (Lilyquist J et al. Gynecol Oncol, 2017 11;147:375-380; Suszynska M et al. J Ovarian Res, 2020 May;13:50). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of RAD51D, and is not expected to trigger nonsense-mediated mRNA decay. This alteration is predicted to result in an alternate stop codon at amino acid position 309 and is predicted to remove only the last 20 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, structural analysis suggests that this truncated region is important for protein function as it contains the RAD51D ATPase domain (Amunugama R et al. J. Biol. Chem. 2012 Mar;287(12):8724-36). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 30, 2020	This variant deletes 1 nucleotide in exon 9 of the RAD51D gene, creating a frameshift and premature translation stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein. This variant is expected to disrupt the amino acid residues Arg300 through Thr328 of the RAD51D protein that encode the C-terminus of the ATPase domain (PMID: 14704354, 19327148, 21111057) and RAD51C interaction domain (PMID: 10749867, 14704354, 19327148). Although functional studies have not been reported for this variant, this variant is likely to disrupt RAD51D function. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51D function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Feb 15, 2024

According to the ACMG SVI adaptation criteria we chose these criteria: PVS1 (strong pathogenic): No NMD expected but last 29 amino acids (ATPase domain) affected , PS4 (supporting pathogenic): In ClinVar and HGMD reported with same phenotype, PM2 (supporting pathogenic): not in gnomAD -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs786202251; hg19: chr17-33428224;