chr17-58709988-G-C

Variant names:

• chr17-58709988-G-C
• rs587782507
• NM_058216.3:c.835G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PP3_Strong

The NM_058216.3(RAD51C):​c.835G>C​(p.Ala279Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,459,778 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005898788: Functional studies indicate this variant impacts protein function [PMID:39299233, 37253112].". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A279G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense, splice_region
• Scores: Splicing: ADA: 0.1252
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6
• Conservation: PhyloP100: 7.47
• Publications: 5 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005898788: Functional studies indicate this variant impacts protein function [PMID: 39299233, 37253112].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

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.835G>C	p.Ala279Pro	missense splice_region	Exon 5 of 9	NP_478123.1	O43502-1
	RAD51C	NR_103872.2		n.710G>C		splice_region non_coding_transcript_exon	Exon 4 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.835G>C	p.Ala279Pro	missense splice_region	Exon 5 of 9	ENSP00000336701.4	O43502-1
	RAD51C	ENST00000482007.5	TSL:1	n.*263G>C		splice_region non_coding_transcript_exon	Exon 4 of 8	ENSP00000433332.1	Q7KZJ0
	RAD51C	ENST00000482007.5	TSL:1	n.*263G>C		3_prime_UTR	Exon 4 of 8	ENSP00000433332.1	Q7KZJ0

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1459778 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 726366

African (AFR) AF: 0.00 AC: 0 AN: 33452

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: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1110164

Other (OTH) AF: 0.00 AC: 0 AN: 60322

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Breast-ovarian cancer, familial, susceptibility to, 3 (2)
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	Fanconi anemia complementation group O (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	1	-	RAD51C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.86		Loss of stability (P = 0.0582)
MVP		0.87
MPC		0.96
ClinPred		0.99	D
GERP RS		5.0
PromoterAI		-0.0056	Neutral
Varity_R		0.95
gMVP		0.91
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.13
dbscSNV1_RF	Benign	0.42
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: rs587782507; hg19: chr17-56787349;