17-58696734-G-T

Variant names:

• chr17-58696734-G-T
• rs1555594622
• NM_058216.3:c.446G>T
• RAD51C p.Gly149Val

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-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_ModerateO6_Supporting

The NM_058216.3(RAD51C):c.446G>T (p.Gly149Val) variant causes a missense change involving the alteration of a 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 0.000000684 (AC=1) in the gnomAD database across 1,461,878 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.84). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G149E: Uncertain_significance (ClinVar VariationId 538761, 2 stars); p.G149= (synonymous): Benign (ClinVar VariationId 3903704, 1 star); p.G149= (synonymous): Likely_benign (ClinVar VariationId 1740875, 2 stars)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.84
• Publications: 0 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: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000001, AC = 1 — absent/extremely rare (O3 moderate [+2])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect

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.446G>T p.Gly149Val	missense	Exon 3 of 9	Prot: NP_478123.1 UniProt:
	RAD51C NR_103872.2		n.446+1545G>T	intron	Intron 2 of 7	Prot:

RAD51C NM_058216.3

MANE Select

HGVSc / HGVSpc.446G>Tp.Gly149Val

Exon rankExon 3 of 9

missense

Prot: NP_478123.1UniProt: O43502-1

RAD51C NR_103872.2

HGVSc / HGVSpn.446+1545G>T

Exon rankIntron 2 of 7

intron

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RAD51C ENST00000337432.9	TSL:1MANE Select	c.446G>T p.Gly149Val	missense	Exon 3 of 9	Prot: ENSP00000336701.4 UniProt:
	RAD51C ENST00000482007.5	TSL:1	n.404+1545G>T	intron	Intron 2 of 7	Prot: ENSP00000433332.1 UniProt:
	RAD51C ENST00000930423.1		c.446G>T p.Gly149Val	missense	Exon 3 of 10	Prot: ENSP00000600482.1 UniProt:

RAD51C ENST00000337432.9

TSL:1MANE Select

HGVSc / HGVSpc.446G>Tp.Gly149Val

Exon rankExon 3 of 9

missense

Prot: ENSP00000336701.4UniProt: O43502-1

RAD51C ENST00000482007.5

TSL:1

HGVSc / HGVSpn.404+1545G>T

Exon rankIntron 2 of 7

intron

Prot: ENSP00000433332.1UniProt: F6SK77

RAD51C ENST00000930423.1

HGVSc / HGVSpc.446G>Tp.Gly149Val

Exon rankExon 3 of 10

missense

Prot: ENSP00000600482.1UniProt: A0ACI8TKF8

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461878	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	34
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
FuncVEP CTI	Pathogenic	0.83
GPN-Star LLR	N/A	-8.8
GPN-Star score	N/A	8.8
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.44	D
Mutation Taster	N/A	5/95	disease causing
MutationAssessor	Pathogenic	4.2	H
PhyloP100	Pathogenic	8.8
popEVE	Benign	-4.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-8.3	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	2.8
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Varity_R	N/A	0.98
VESM-3B	Benign	-13

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.090
SpliceAI score (max)	Benign	0.13	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: rs1555594622;

hg19: chr17-56774095;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar