17-35103297-C-T

Variant names:

• chr17-35103297-C-T
• rs28363283
• NM_002878.4:c.695G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000345365.11(RAD51D):​c.695G>A​(p.Arg232Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000859 in 1,611,706 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R232L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (2 hom.)
• Consequence: RAD51D ENST00000345365.11 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.359
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006022185).
• BP6: Variant 17-35103297-C-T is Benign according to our data. Variant chr17-35103297-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0042 (640/152242) while in subpopulation AFR AF = 0.0137 (570/41536). AF 95% confidence interval is 0.0128. There are 6 homozygotes in GnomAd4. There are 290 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 640 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000345365.11. 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.695G>A	p.Arg232Gln	missense	Exon 8 of 10	NP_002869.3
	RAD51D	NM_001142571.2		c.755G>A	p.Arg252Gln	missense	Exon 8 of 10	NP_001136043.1
	RAD51D	NM_133629.3		c.359G>A	p.Arg120Gln	missense	Exon 5 of 7	NP_598332.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51D	ENST00000345365.11	TSL:1 MANE Select	c.695G>A	p.Arg232Gln	missense	Exon 8 of 10	ENSP00000338790.6
	RAD51D	ENST00000586186.3	TSL:1	c.560G>A	p.Arg187Gln	missense	Exon 7 of 9	ENSP00000468273.3
	ENSG00000267618	ENST00000593039.5	TSL:2	c.218G>A	p.Arg73Gln	missense	Exon 4 of 7	ENSP00000466834.1

Frequencies

GnomAD3 genomes AF: 0.00419 AC: 638 AN: 152124 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00127 AC: 312 AN: 245490 AF XY: 0.000958

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00142

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000207

Gnomad OTH exome AF: 0.000668

GnomAD4 exome AF: 0.000510 AC: 745 AN: 1459464 Hom.: 2 Cov.: 32 AF XY: 0.000451 AC XY: 327 AN XY: 725784

African (AFR) AF: 0.0144 AC: 482 AN: 33462

American (AMR) AF: 0.00156 AC: 69 AN: 44328

Ashkenazi Jewish (ASJ) AF: 0.000730 AC: 19 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53224

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5722

European-Non Finnish (NFE) AF: 0.000102 AC: 113 AN: 1111098

Other (OTH) AF: 0.000846 AC: 51 AN: 60300

GnomAD4 genome AF: 0.00420 AC: 640 AN: 152242 Hom.: 6 Cov.: 32 AF XY: 0.00390 AC XY: 290 AN XY: 74430

African (AFR) AF: 0.0137 AC: 570 AN: 41536

American (AMR) AF: 0.00346 AC: 53 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68010

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00171 Hom.: 6

Bravo AF: 0.00480

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00128 AC: 156

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Breast-ovarian cancer, familial, susceptibility to, 4 (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.36
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.10
Sift	Benign	0.30	T
Sift4G	Benign	0.18	T
Polyphen		0.060	B
Vest4		0.18
MVP		0.76
MPC		0.41
ClinPred		0.013	T
GERP RS		0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.52
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs28363283; hg19: chr17-33430316; COSMIC: COSV107428897;