rs587781309

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_058216.3(RAD51C):c.80T>C(p.Leu27Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L27L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: 6.13

Publications

6 publications found

Variant links:

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):

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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RAD51C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

PP5

Variant 17-58692723-T-C is Pathogenic according to our data. Variant chr17-58692723-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 140837.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3 link	c.80T>C	p.Leu27Pro	missense_variant	Exon 1 of 9	ENST00000337432.9	NP_478123.1	O43502-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9 link	c.80T>C	p.Leu27Pro	missense_variant	Exon 1 of 9	1	NM_058216.3	ENSP00000336701.4		O43502-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 3

Pathogenic:1Uncertain:2

Nov 25, 2024

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 39299233, 37253112, 36099300]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Dec 21, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 13, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Apr 23, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.L27P variant (also known as c.80T>C), located in coding exon 1 of the RAD51C gene, results from a T to C substitution at nucleotide position 80. The leucine at codon 27 is replaced by proline, an amino acid with similar properties. This variant was identified in 1/3447 cases of invasive epithelial ovarian cancer and in 0/4812 unaffected controls (Song H et al. J Clin Oncol, 2015 Sep;33:2901-7). In multiple assays testing RAD51C function, this alteration showed an abnormal read-out (Hu C et al. Cancer Res, 2023 Aug;83:2557-2571; Prakash R et al. Proc Natl Acad Sci U S A, 2022 Sep;119:e2202727119). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Apr 07, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces leucine with proline at codon 27 of the RAD51C protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant significantly reduced homologous recombination activity (PMID: 36099300, 37253112), sensitivity to cisplatin and olaparib (PMID: 37253112), and impacts function (PMID: 39299233). Studies have also shown that this variant does not disrupt interactions with RAD51B and XRCC3, disrupts interactions with XRCC2, and conflicting results as to whether this variant impacts interactions with RAD51D (PMID: 36099300, 37253112). This variant has been reported in two individuals affected with ovarian cancer (PMID: 26261251, 36099300) and in an individual affected with breast cancer (PMID: 35127508). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:1

Dipartimento Di Medicina Di Precisione, Università Degli Studi Della Campania Luigi Vanvitelli

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant c.80T>C (p.Leu27Pro) in RAD51C, located in exon 1, results in the substitution of a conserved leucine residue within a critical domain involved in homologous recombination repair. In silico predictions (e.g., REVEL, CADD, PolyPhen-2) support a deleterious effect on protein function. The variant is rare in population databases and has been reported in patients with hereditary breast and ovarian cancer. Based on ACMG/AMP criteria (PM2, PP3, PP4), it is classified as likely pathogenic. -

not provided

Uncertain:1

Nov 22, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28829762, 26261251, 36011273, 34284872) -

Fanconi anemia complementation group O

Uncertain:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 27 of the RAD51C protein (p.Leu27Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26261251, 34284872, 35127508, 36099300). ClinVar contains an entry for this variant (Variation ID: 140837). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RAD51C protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RAD51C function (PMID: 36099300, 37253112). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.41

T;D;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.85

D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.14

MutationAssessor

Uncertain

2.8

.;M;M

PhyloP100

6.1

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.1

.;D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.86

MutPred

0.88

Gain of disorder (P = 0.0084);Gain of disorder (P = 0.0084);Gain of disorder (P = 0.0084);

MVP

0.98

MPC

1.1

ClinPred

1.0

GERP RS

4.7

PromoterAI

0.019

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.78

gMVP

0.87

Mutation Taster

=31/69

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over