17-35107379-C-T

Variant names:

• chr17-35107379-C-T
• rs786203407
• NM_002878.4:c.332G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The ENST00000345365.11(RAD51D):​c.332G>A​(p.Ser111Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,542 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S111R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RAD51D ENST00000345365.11 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.58
• Publications: 0 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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 37 uncertain in ENST00000345365.11
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.332G>A	p.Ser111Asn	missense	Exon 4 of 10	NP_002869.3
	RAD51D	NM_001142571.2		c.392G>A	p.Ser131Asn	missense	Exon 4 of 10	NP_001136043.1
	RAD51D	NR_037711.2		n.358G>A		non_coding_transcript_exon	Exon 3 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51D	ENST00000345365.11	TSL:1 MANE Select	c.332G>A	p.Ser111Asn	missense	Exon 4 of 10	ENSP00000338790.6
	RAD51D	ENST00000586186.3	TSL:1	c.332G>A	p.Ser111Asn	missense	Exon 4 of 9	ENSP00000468273.3
	RAD51D	ENST00000585343.5	TSL:1	n.*154G>A		non_coding_transcript_exon	Exon 4 of 6	ENSP00000465007.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406542 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 702498

African (AFR) AF: 0.00 AC: 0 AN: 32122

American (AMR) AF: 0.00 AC: 0 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25830

East Asian (EAS) AF: 0.00 AC: 0 AN: 39426

South Asian (SAS) AF: 0.00 AC: 0 AN: 85142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 9.42e-7 AC: 1 AN: 1061736

Other (OTH) AF: 0.00 AC: 0 AN: 58586

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Hereditary cancer-predisposing syndrome (3)
-	1	-	Breast-ovarian cancer, familial, susceptibility to, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		1.6
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.58		Loss of glycosylation at S111 (P = 0.003)
MVP		0.98
MPC		0.44
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.82
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.66		Position offset: 4

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

Other links and lift over

dbSNP: rs786203407; hg19: chr17-33434398;