rs1555568473

chr17-35107368-G-Achr17-35107368-G-Cchr17-35107368-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_002878.4(RAD51D):c.343C>T(p.Gln115Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q115Q) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAD51D NM_002878.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.97

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 19 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-35107368-G-A is Pathogenic according to our data. Variant chr17-35107368-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 472599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51D	NM_002878.4	c.343C>T	p.Gln115Ter	stop_gained, splice_region_variant	4/10	ENST00000345365.11
RAD51L3-RFFL	NR_037714.1	n.233-887C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51D	ENST00000345365.11	c.343C>T	p.Gln115Ter	stop_gained, splice_region_variant	4/10	1	NM_002878.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jan 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2023	This missense variant replaces glutamine with a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. In addition, this variant has been shown to affect splicing in a mini-gene assay and in a breast cancer cell line, resulting in multiple abnormal transcripts including out-of-frame deletion of exon 4 or exons 4-5, as well as in-frame deletion of exons 3-5 that encode a functionally important ATPase domain (PMID: 34200360). 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 Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 30, 2020	The p.Q115* pathogenic mutation (also known as c.343C>T), located in coding exon 4 of the RAD51D gene, results from a C to T substitution at nucleotide position 343. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 13, 2023	This sequence change creates a premature translational stop signal (p.Gln115*) in the RAD51D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51D are known to be pathogenic (PMID: 21822267). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 472599). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 04, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	47
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A;A;A;A;D;D
Vest4		0.86
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.75		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555568473; hg19: chr17-33434387;