chr17-35118500-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_002878.4(RAD51D):c.263+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000186 in 1,612,760 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 splice_donor, intron

Scores

Splicing: ADA: 0.9918

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3

Conservation

PhyloP100: 6.25

Variant links:

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 links:

ENSG00000267618 (HGNC:):

ENSG00000267618 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-35118500-C-T is Pathogenic according to our data. Variant chr17-35118500-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 480542.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=3}. Variant chr17-35118500-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51D	NM_002878.4 link	c.263+1G>A		splice_donor_variant, intron_variant	Intron 3 of 9	ENST00000345365.11	NP_002869.3	O75771-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11 link	c.263+1G>A		splice_donor_variant, intron_variant	Intron 3 of 9	1	NM_002878.4	ENSP00000338790.6		O75771-1
ENSG00000267618	ENST00000593039.5 link	c.3+2791G>A		intron_variant	Intron 1 of 6	2		ENSP00000466834.1		K7EN88

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460452

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726644

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4

Pathogenic:3

Nov 27, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 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 3 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 pancreatic cancer, ovarian cancer and/or breast cancer (PMID: 26261251, 26720728, 29506128, 32107557). ClinVar contains an entry for this variant (Variation ID: 480542). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (internal data). 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. -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Sep 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.263+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 3 of the RAD51D gene. This alteration has been identified in a 64 year old woman with ovarian cancer (Norquist BM et al. JAMA Oncol, 2016 Apr;2:482-90) and in an unaffected 53 year old patient with a family history of ovarian cancer (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). 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, direct evidence is insufficient at this time (Ambry internal data). In addition, RNA data has shown that exon 3 is 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. -

Apr 03, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Oct 27, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in skipping of the adjacent exon 3; however, RNA studies demonstrate naturally occurring isoforms lacking exon 3 in multiple tissues (Davy 2017, Brandao 2019); Not observed at significant frequency in large population cohorts (Lek 2016); Observed in individuals with personal and family history of ovarian cancer or with pancreatic cancer (Song 2015, Lowery 2018); This variant is associated with the following publications: (PMID: 29506128, 26261251) -

RAD51D-related disorder

Uncertain:1

Sep 27, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RAD51D c.263+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been previously reported in individuals with breast and/or ovarian cancer (Song et al. 2015. PubMed ID: 26261251; Yang et al. 2020. PubMed ID: 32107557, Supplementary Table 6; Norquist et al. 2016. PubMed ID: 26720728, eTable 1), and observed in a cohort of patients with exocrine pancreatic neoplasms (Lowery et al. 2018. PubMed ID: 29506128). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has conflicting interpretations of pathogenicity in ClinVar ranging from likely pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/480542/). Although we suspect that c.263+1G>A variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.93

GERP RS

4.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.96

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.26

Position offset: -5

DS_DL_spliceai

0.96

Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over