Genetic Variant RAD51C:p.Met10Arg (chr17-58692672-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_058216.3(RAD51C):c.29T>G(p.Met10Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,888 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 6.13

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3 link	c.29T>G	p.Met10Arg	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.29T>G	p.Met10Arg	missense_variant	Exon 1 of 9	1	NM_058216.3	ENSP00000336701.4		O43502-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251448

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RAD51C: PM2:Supporting, BS3:Supporting -

Nov 13, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2024

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: 25470109, 23117857, 37253112, 38330859, 29522266, 21750962) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Mar 18, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with arginine at codon 10 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 21750962). This variant has been identified in 2/251448 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Sep 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M10R variant (also known as c.29T>G), located in coding exon 1 of the RAD51C gene, results from a T to G substitution at nucleotide position 29. The methionine at codon 10 is replaced by arginine, an amino acid with similar properties. This alteration was identified in 1/232 ovarian cancer patients not selected for family history (Vuorela M et al. Breast Cancer Res. Treat. 2011 Dec;130:1003-10). This alteration was also detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Breast-ovarian cancer, familial, susceptibility to, 3

Uncertain:2

Aug 08, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3

Uncertain:1

Oct 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group O

Uncertain:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 10 of the RAD51C protein (p.Met10Arg). This variant is present in population databases (rs730881936, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 21750962). ClinVar contains an entry for this variant (Variation ID: 182841). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect RAD51C function (PMID: 37253112). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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

Benign

0.21

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Benign

0.039

T;T;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.48

T;T;T

M_CAP

Benign

0.081

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.5

.;M;M

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.4

.;N;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.017

.;D;D

Sift4G

Uncertain

0.030

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.88

MVP

0.86

MPC

1.0

ClinPred

0.88

GERP RS

5.6

Varity_R

0.63

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over