17-35103263-C-CA

Position:

• chr17-35103263-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002878.4(RAD51D):​c.728_729insT​(p.Met243IlefsTer84) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51D NM_002878.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.98

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-35103263-C-CA is Pathogenic according to our data. Variant chr17-35103263-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 410560.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51D	NM_002878.4	c.728_729insT	p.Met243IlefsTer84	frameshift_variant	8/10	ENST00000345365.11
RAD51L3-RFFL	NR_037714.1	n.480_481insT		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51D	ENST00000345365.11	c.728_729insT	p.Met243IlefsTer84	frameshift_variant	8/10	1	NM_002878.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 22, 2017

In summary, this variant is a rare frameshift variant that is expected to disrupt an important functional domain of 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 frameshift is expected to partially disrupt the C-terminus of the ATPase domain of the RAD51D protein (PMID: 14704354, 19327148, 21111057), which is required for interacting with RAD51C to assist DNA repair activity (PMID: 14704354, 19327148). While functional studies have not been reported for this particular variant, a truncating variant in the C- terminal region was found to segregate in three family members with ovarian cancer and family history of ovarian and breast cancers (Invitae database), suggesting that disruption of this region of the RAD51D protein is causative of disease. 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. This sequence change inserts 1 nucleotide in exon 8 of the RAD51D mRNA (c.728dupT), causing a frameshift at codon 243. This creates a premature translational stop signal in the last exon of the RAD51D mRNA (p.Met243Ilefs*84). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 86 amino acids of the RAD51D protein. -

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: rs1060502958; hg19: chr17-33430282;