chr17-35101355-TG-T

Variant names:

• chr17-35101355-TG-T
• rs587780105
• NM_002878.4:c.748delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_002878.4(RAD51D):​c.748delC​(p.His250ThrfsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000253 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H250H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: RAD51D NM_002878.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 4.17
• Publications: 7 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):

• RAD51D-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 4

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000267618 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-35101355-TG-T is Pathogenic according to our data. Variant chr17-35101355-TG-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 127894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 37 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51D	NM_002878.4	MANE Select	c.748delC	p.His250ThrfsTer2	frameshift	Exon 9 of 10	NP_002869.3
	RAD51D	NM_001142571.2		c.808delC	p.His270ThrfsTer2	frameshift	Exon 9 of 10	NP_001136043.1	O75771-8
	RAD51D	NM_133629.3		c.412delC	p.His138ThrfsTer2	frameshift	Exon 6 of 7	NP_598332.1	O75771-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51D	ENST00000345365.11	TSL:1 MANE Select	c.748delC	p.His250ThrfsTer2	frameshift	Exon 9 of 10	ENSP00000338790.6	O75771-1
	RAD51D	ENST00000586186.3	TSL:1	c.613delC	p.His205ThrfsTer2	frameshift	Exon 8 of 9	ENSP00000468273.3	O75771-4
	ENSG00000267618	ENST00000593039.5	TSL:2	c.271delC	p.His91ThrfsTer2	frameshift	Exon 5 of 7	ENSP00000466834.1	K7EN88

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251058 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461544 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727052

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Breast-ovarian cancer, familial, susceptibility to, 4 (3)
3	-	-	not provided (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Familial ovarian cancer (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587780105; hg19: chr17-33428374;