chr17-35101205-CG-C

Variant names:

• chr17-35101205-CG-C
• rs786202251
• NM_002878.4:c.898delC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_002878.4(RAD51D):​c.898delC​(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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51D NM_002878.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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]

ENSG00000267618 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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. Fraction of 0.0902 CDS is truncated, and there are 2 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 rank	MANE	Protein	UniProt
RAD51D	NM_002878.4	c.898delC	p.Arg300AspfsTer10	frameshift_variant	Exon 9 of 10	ENST00000345365.11	NP_002869.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.898delC	p.Arg300AspfsTer10	frameshift_variant	Exon 9 of 10	1	NM_002878.4	ENSP00000338790.6
ENSG00000267618	ENST00000593039.5	c.421delC	p.Arg141AspfsTer21	frameshift_variant	Exon 5 of 7	2		ENSP00000466834.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

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	May 28, 2024	This sequence change creates a premature translational stop signal (p.Arg300Aspfs*10) in the RAD51D gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the RAD51D protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 28888541). ClinVar contains an entry for this variant (Variation ID: 185528). This variant disrupts the ATPase domain and RAD51C interaction domain of the RAD51D protein, which are necessary for the DNA repair activity (PMID: 14704354, 19327148, 21111057, 10749867). While functional studies have not been performed to directly test the effect of this variant on RAD51D protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 04, 2024	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

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. -
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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jul 17, 2024

The RAD51D c.898del (p.Arg300Aspfs*10) variant alters the translational reading frame of the RAD51D mRNA and is predicted to cause the premature termination of RAD51D protein synthesis. While not expected to result in nonsense-mediated decay, the disrupted region is considered important to protein function (PMIDs: 10749867 (2000), 14704354 (2004), 21111057 (2011)). This variant has been reported in the published literature in individuals with breast cancer (PMID: 35884425 (2022)) and ovarian cancer (PMID: 28888541 (2017)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, 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;