chr17-58696734-G-C

Variant names:

• chr17-58696734-G-C
• rs1555594622
• NM_058216.3:c.446G>C
• RAD51C p.Gly149Ala

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_058216.3(RAD51C):c.446G>C (p.Gly149Ala) 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 is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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)
• 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 2 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 = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

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>C p.Gly149Ala	missense	Exon 3 of 9	Prot: NP_478123.1 UniProt:
	RAD51C NR_103872.2		n.446+1545G>C	intron	Intron 2 of 7	Prot:

RAD51C NM_058216.3

MANE Select

HGVSc / HGVSpc.446G>Cp.Gly149Ala

Exon rankExon 3 of 9

missense

Prot: NP_478123.1UniProt: O43502-1

RAD51C NR_103872.2

HGVSc / HGVSpn.446+1545G>C

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>C p.Gly149Ala	missense	Exon 3 of 9	Prot: ENSP00000336701.4 UniProt:
	RAD51C ENST00000482007.5	TSL:1	n.404+1545G>C	intron	Intron 2 of 7	Prot: ENSP00000433332.1 UniProt:
	RAD51C ENST00000930423.1		c.446G>C p.Gly149Ala	missense	Exon 3 of 10	Prot: ENSP00000600482.1 UniProt:

RAD51C ENST00000337432.9

TSL:1MANE Select

HGVSc / HGVSpc.446G>Cp.Gly149Ala

Exon rankExon 3 of 9

missense

Prot: ENSP00000336701.4UniProt: O43502-1

RAD51C ENST00000482007.5

TSL:1

HGVSc / HGVSpn.404+1545G>C

Exon rankIntron 2 of 7

intron

Prot: ENSP00000433332.1UniProt: F6SK77

RAD51C ENST00000930423.1

HGVSc / HGVSpc.446G>Cp.Gly149Ala

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:	AC:	Hom:	AN:	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	26
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
FuncVEP CTI	Pathogenic	0.45
GPN-Star LLR	N/A	-6.5
GPN-Star score	N/A	6.5
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.37	T
Mutation Taster	N/A	51/49	polymorphism
MutationAssessor	Pathogenic	3.5	H
PhyloP100	Pathogenic	8.8
popEVE	Benign	-3.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.5	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	2.8
REVEL	Uncertain	0.48
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.016	D
Varity_R	N/A	0.82
VESM-3B	Benign	-10

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.050
SpliceAI score (max)	Benign	0.020	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