17-58692778-G-A

Variant names:

• chr17-58692778-G-A
• rs371608994
• NM_058216.3:c.135G>A
• RAD51C p.Glu45Glu

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_SupportingB4_Strong

The NM_058216.3(RAD51C):c.135G>A (p.Glu45Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The gene RAD51C is a tumor suppressor gene (CancerMine: 5 TSG, 2 oncogene, 1 driver citations). The gene RAD51C is a known oncogene (CancerMine: 5 TSG, 2 oncogene, 1 driver citations). The gene RAD51C is a cancer driver gene (CancerMine: 5 TSG, 2 oncogene, 1 driver citations). The variant allele was found at a cumulative frequency of 0.0000041 (AC=6) in the gnomAD database across 1,461,872 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RAD51C NM_058216.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.654
• Publications: 1 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fanconi anemia complementation group O

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000015 — very rare (O3 supporting [+1])
	B4Synonymous/intronic, no splicing impact		Synonymous/intronic variant with confirmed no splicing impact (B4 strong); Synonymous variant — splicing algorithms confirm no impact on splicing (B4 strong [-4])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_058216.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RAD51C NM_058216.3	MANE Select	c.135G>A p.Glu45Glu	synonymous	Exon 1 of 9	Prot: NP_478123.1 UniProt:
	RAD51C NM_002876.4		c.135G>A p.Glu45Glu	synonymous	Exon 1 of 2	Prot: NP_002867.1 UniProt:
	RAD51C NR_103872.2		n.177G>A	non_coding_transcript_exon	Exon 1 of 8	Prot:

RAD51C NM_058216.3

MANE Select

HGVSc / HGVSpc.135G>Ap.Glu45Glu

Exon rankExon 1 of 9

synonymous

Prot: NP_478123.1UniProt: O43502-1

RAD51C NM_002876.4

HGVSc / HGVSpc.135G>Ap.Glu45Glu

Exon rankExon 1 of 2

synonymous

Prot: NP_002867.1UniProt: O43502-2

RAD51C NR_103872.2

HGVSc / HGVSpn.177G>A

Exon rankExon 1 of 8

non_coding_transcript_exon

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RAD51C ENST00000337432.9	TSL:1MANE Select	c.135G>A p.Glu45Glu	synonymous	Exon 1 of 9	Prot: ENSP00000336701.4 UniProt:
	RAD51C ENST00000421782.3	TSL:1	c.135G>A p.Glu45Glu	synonymous	Exon 1 of 2	Prot: ENSP00000391450.2 UniProt:
	RAD51C ENST00000482007.5	TSL:1	n.135G>A	non_coding_transcript_exon	Exon 1 of 8	Prot: ENSP00000433332.1 UniProt:

RAD51C ENST00000337432.9

TSL:1MANE Select

HGVSc / HGVSpc.135G>Ap.Glu45Glu

Exon rankExon 1 of 9

synonymous

Prot: ENSP00000336701.4UniProt: O43502-1

RAD51C ENST00000421782.3

TSL:1

HGVSc / HGVSpc.135G>Ap.Glu45Glu

Exon rankExon 1 of 2

synonymous

Prot: ENSP00000391450.2UniProt: O43502-2

RAD51C ENST00000482007.5

TSL:1

HGVSc / HGVSpn.135G>A

Exon rankExon 1 of 8

non_coding_transcript_exon

Prot: ENSP00000433332.1UniProt: F6SK77

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152236	Cov:32
GnomAD4 exome	AF: 0.00000410	AC:6	Hom:0	AN:1461872	Cov:32
GnomAD4 genome Warning	AF: 0.00000657	AC:1	Hom:0	AN:152236	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16838	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
BayesDel_noAF	Benign	-0.44
CADD	Benign	10
DANN	Benign	0.93
GPN-Star LLR	N/A	-1.7
GPN-Star score	N/A	1.7
PhyloP100	Benign	0.65
PromoterAI	N/A	-0.026	Neutral
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs371608994;

hg19: chr17-56770139;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar