chr17-58703329-G-T

Variant names:

• chr17-58703329-G-T
• rs755849719
• NM_058216.3:c.705G>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM1 PM2 PP3_Strong PP5

The NM_058216.3(RAD51C):​c.705G>T​(p.Lys235Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,611,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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). ClinVar reports functional evidence for this variant: "SCV000255192: Experimental studies have shown that this missense change does not substantially affect RAD51C function (PMID:37253112). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID:33333735" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K235E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:3
• Conservation: PhyloP100: 8.24
• Publications: 7 publications found

Genes affected

RAD51C (HGNC:9820): (RAD51 paralog C) This gene is a member of the RAD51 family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51 and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Mutations in this gene are associated with Fanconi anemia-like syndrome. This gene is one of four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

RAD51C Gene-Disease associations (from GenCC):

• RAD51C-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Fanconi anemia complementation group O

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000255192: Experimental studies have shown that this missense change does not substantially affect RAD51C function (PMID: 37253112). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 33333735; internal data).; SCV000274447: RNA studies from lymphoblastoid cell lines (LCLs) from the carrier of this alteration showed absence of the entire exon 4 (Alenezi WM et al. Cancers (Basel), 2022 Apr;14). In another RNA study, this variant was associated with exon 4 skipping (Sanoguera-Miralles L et al. Cancers (Basel), 2020 Dec;12). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data).; SCV006063236: RNA studies conducted in carrier-derived lymphoblastoid cell lines and minigene assays have shown that this variant causes out-of-frame skipping of exon 4 (PMID: 33333735).; SCV001805733: Demonstrated by functional data to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Sanoguera-Miralles 2020); PMID: 34923718, 14704354, 33333735
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 38 uncertain in NM_058216.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-58703329-G-T is Pathogenic according to our data. Variant chr17-58703329-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216807.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058216.3. 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
	RAD51C	NM_058216.3	MANE Select	c.705G>T	p.Lys235Asn	missense splice_region	Exon 4 of 9	NP_478123.1	O43502-1
	RAD51C	NR_103872.2		n.580G>T		splice_region non_coding_transcript_exon	Exon 3 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.705G>T	p.Lys235Asn	missense splice_region	Exon 4 of 9	ENSP00000336701.4	O43502-1
	RAD51C	ENST00000482007.5	TSL:1	n.*133G>T		splice_region non_coding_transcript_exon	Exon 3 of 8	ENSP00000433332.1	Q7KZJ0
	RAD51C	ENST00000482007.5	TSL:1	n.*133G>T		3_prime_UTR	Exon 3 of 8	ENSP00000433332.1	Q7KZJ0

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152104 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251038 AF XY: 0.00000737

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459300 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726108

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110126

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152104 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 3 (1)
1	-	-	Fanconi anemia complementation group O (1)
-	1	-	Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 (1)
-	1	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.90	L
PhyloP100		8.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.12
Sift	Benign	0.063	T
Sift4G	Benign	0.42	T
Polyphen		0.12	B
Vest4		0.69
MutPred		0.48		Loss of helix (P = 0.0167)
MVP		0.87
MPC		0.34
ClinPred		0.55	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.50
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: 0

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

Other links and lift over

dbSNP: rs755849719; hg19: chr17-56780690;