chr17-58692778-G-C

Variant names:

• chr17-58692778-G-C
• rs371608994
• NM_058216.3:c.135G>C
• RAD51C p.Glu45Asp

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4_ModerateBP6

The NM_058216.3(RAD51C):c.135G>C (p.Glu45Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,872 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000299. 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 (REVEL) 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 (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E45A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 492362); p.E45= (synonymous): Benign/Likely_benign (ClinVar VariationId 480513, 2 stars); p.E45G: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 140940); p.E45K: Uncertain_significance (ClinVar VariationId 538777, 2 stars); p.E45K: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 1770324) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000299 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

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>C p.Glu45Asp	missense	Exon 1 of 9	Prot: NP_478123.1 UniProt:
	RAD51C NM_002876.4		c.135G>C p.Glu45Asp	missense	Exon 1 of 2	Prot: NP_002867.1 UniProt:
	RAD51C NR_103872.2		n.177G>C	non_coding_transcript_exon	Exon 1 of 8	Prot:

RAD51C NM_058216.3

MANE Select

HGVSc / HGVSpc.135G>Cp.Glu45Asp

Exon rankExon 1 of 9

missense

Prot: NP_478123.1UniProt: O43502-1

RAD51C NM_002876.4

HGVSc / HGVSpc.135G>Cp.Glu45Asp

Exon rankExon 1 of 2

missense

Prot: NP_002867.1UniProt: O43502-2

RAD51C NR_103872.2

HGVSc / HGVSpn.177G>C

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>C p.Glu45Asp	missense	Exon 1 of 9	Prot: ENSP00000336701.4 UniProt:
	RAD51C ENST00000421782.3	TSL:1	c.135G>C p.Glu45Asp	missense	Exon 1 of 2	Prot: ENSP00000391450.2 UniProt:
	RAD51C ENST00000482007.5	TSL:1	n.135G>C	non_coding_transcript_exon	Exon 1 of 8	Prot: ENSP00000433332.1 UniProt:

RAD51C ENST00000337432.9

TSL:1MANE Select

HGVSc / HGVSpc.135G>Cp.Glu45Asp

Exon rankExon 1 of 9

missense

Prot: ENSP00000336701.4UniProt: O43502-1

RAD51C ENST00000421782.3

TSL:1

HGVSc / HGVSpc.135G>Cp.Glu45Asp

Exon rankExon 1 of 2

missense

Prot: ENSP00000391450.2UniProt: O43502-2

RAD51C ENST00000482007.5

TSL:1

HGVSc / HGVSpn.135G>C

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152236	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251336	Cov:
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461872	Cov:32
GnomAD4 genome Warning	AF: 0.0000131	AC:2	Hom:0	AN:152236	Cov:32
TOPMed (Bravo)	AF: 0.0000227	AC:6	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16838	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000238	1	41956	0.0000299	2	66886

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Fanconi anemia complementation group O (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.83
DEOGEN2	Benign	0.0083	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.73	D
FuncVEP CTI	Benign	0.0034
GPN-Star LLR	N/A	-3.9
GPN-Star score	N/A	3.9
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	90/10	polymorphism
MutationAssessor	Benign	1.4	L
PhyloP100	Benign	0.65
popEVE	Benign	-3.1
PrimateAI	Uncertain	0.60	T
PromoterAI	N/A	0.053	Neutral
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.023
Sift	Benign	0.51	T
Sift4G	Benign	0.40	T
Varity_R	N/A	0.041
VESM-3B	Benign	-5.2

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	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;

COSMIC: COSV53619785;

COSMIC: COSV53619785;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar