17-35107364-A-G

Variant names:

• chr17-35107364-A-G
• rs876659394
• NM_002878.4:c.345+2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_002878.4(RAD51D):​c.345+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000719 in 1,391,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: RAD51D NM_002878.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9885
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 6.39
• Publications: 4 publications found

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]

RAD51D Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 4

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000267618 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08308004 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of 6, new splice context is: catGTgagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-35107364-A-G is Pathogenic according to our data. Variant chr17-35107364-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 231839.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002878.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51D	NM_002878.4	MANE Select	c.345+2T>C		splice_donor intron	N/A	NP_002869.3
	RAD51D	NM_001142571.2		c.405+2T>C		splice_donor intron	N/A	NP_001136043.1
	RAD51D	NM_133629.3		c.145-883T>C		intron	N/A	NP_598332.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51D	ENST00000345365.11	TSL:1 MANE Select	c.345+2T>C		splice_donor intron	N/A	ENSP00000338790.6
	RAD51D	ENST00000586186.3	TSL:1	c.345+2T>C		splice_donor intron	N/A	ENSP00000468273.3
	ENSG00000267618	ENST00000593039.5	TSL:2	c.4-883T>C		intron	N/A	ENSP00000466834.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391178 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 695206

African (AFR) AF: 0.00 AC: 0 AN: 31798

American (AMR) AF: 0.00 AC: 0 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25742

East Asian (EAS) AF: 0.00 AC: 0 AN: 39330

South Asian (SAS) AF: 0.00 AC: 0 AN: 84784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 9.54e-7 AC: 1 AN: 1047794

Other (OTH) AF: 0.00 AC: 0 AN: 58092

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Mar 18, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 4 of the RAD51D gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RAD51D are known to be pathogenic (PMID: 21822267). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with ovarian cancer (PMID: 28888541). ClinVar contains an entry for this variant (Variation ID: 231839). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

Jan 04, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Breast and/or ovarian cancer Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:1

Oct 06, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant demonstrated to result in aberrant splicing in a gene for which loss of function is a known mechanism of disease (Bueno-Martinez et al., 2021); Not observed in large population cohorts (gnomAD); Identified in at least one individual with ovarian cancer (Lilyquist et al., 2017); This variant is associated with the following publications: (PMID: 34200360, 33471991, 28888541, 32295079)

Hereditary cancer-predisposing syndrome Uncertain:1

Aug 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.345+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 4 in the RAD51D gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. However, RNA studies have shown that exons 3 through 5 are excluded in several naturally occurring RAD51D isoforms (Davy G et al. Eur. J. Hum. Genet., 2017 10;25:1147-1154; Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		6.4
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.59
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.92		Position offset: 2

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

Other links and lift over

dbSNP: rs876659394; hg19: chr17-33434383;