17-58696702-G-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong

The NM_058216.3(RAD51C):c.414G>C(p.Leu138Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,040 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 2.76

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 Likely_pathogenic. Variant got 9 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.77

PP5

Variant 17-58696702-G-C is Pathogenic according to our data. Variant chr17-58696702-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58696702-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3 link	c.414G>C	p.Leu138Phe	missense_variant	Exon 3 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.414G>C	p.Leu138Phe	missense_variant	Exon 3 of 9	1	NM_058216.3	ENSP00000336701.4		O43502-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251476

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135908

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727224

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:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:3

Apr 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 3

Pathogenic:2Other:1

May 01, 2010

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 06, 2023

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: 22167183]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20400964, 24993905]. -

May 15, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

May 06, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: impaired response to DNA damage, reduced RAD51 foci formation, impaired protein interaction with RAD51 paralogs, increased chromosome aberrations, and inability to rescue cell survival (PMID: 20400964, 22167183, 36099300); Observed in individuals with history consistent with pathogenic variants in this gene (PMID: 22538716, 22451500, 27328445, 35565380); 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: 20952512, 27328445, 22451500, 25470109, 26678223, 24993905, 26354865, 23438602, 24141787, 21537932, 28829762, 25292178, 22538716, 36562461, 36099300, 14704354, 22167183, 20400964, 35565380, 30612635, 29922827, 28888541) -

Nov 02, 2014

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Oct 26, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L138F variant (also known as c.414G>C), located in coding exon 3 of the RAD51C gene, results from a G to C substitution at nucleotide position 414. The leucine at codon 138 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was previously described and found to co-segregate in one German breast and ovarian cancer family, and LOH was present in 3/3 tumors available (2 ovarian cancers and 1 breast cancer) (Meindl A et al. Nat. Genet. 2010 May; 42(5):410-4). This alteration was also reported in a Spanish female diagnosed with ovarian cancer at age 62; one of her sisters was diagnosed with breast cancer at age 37 and a second sister, who also had this variant, was diagnosed with bilateral breast cancer at ages 64 and 72, and was not reported in 550 healthy controls with no family history of cancer (Osorio A et al. Hum. Mol. Genet. 2012 Jul; 21(13):2889-98). This variant has been identified in multiple individuals diagnosed with ovarian cancer (Alenezi WM et al. Cancers (Basel), 2022 Apr;14; Loveday C et al. Nat Genet, 2012 Apr;44:475-6). In multiple assays testing RAD51C function, this variant showed functionally abnormal results (Meindl A et al. Nat. Genet. 2010 May; 42(5):410-4; Somyajit K et al. J. Biol. Chem. 2012 Jan; 287(5):3366-80; Park JY et al. Oncogene 2014 Oct; 33(40):4803-12; Somyajit K et al. Carcinogenesis 2015 Jan; 36(1):13-24; Somyajit K et al. Nucleic Acids Res. 2015 Nov; 43(20):9835-55; Prakash R et al. Proc Natl Acad Sci U S A, 2022 Sep;119:e2202727119; Hu C et al. Cancer Res, 2023 Aug;83:2557-2571). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Jan 03, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with phenylalanine at codon 138 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Multiple functional studies have shown that the mutant protein exhibits significantly reduced ability to bind BRCA2, RAD51D, RAD51B, and XRCC3, reduced homologous recombination activity, and inability to complement RAD51C deficiency in cell survival assay (PMID: 20400964, 22167183, 24141787, 25292178, 36099300). This variant has been reported in five unrelated individuals affected with ovarian cancer with family history of ovarian cancer and/or breast cancer (PMID: 20400964, 22451500, 24993905, 35565380). This variant has also been reported in an individual with sporadic, early-onset ovarian cancer (PMID: 35565380) and in an individual with triple-negative breast cancer (PMID: 27328445). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Fanconi anemia complementation group O

Pathogenic:2

Jun 14, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 138 of the RAD51C protein (p.Leu138Phe). This variant is present in population databases (rs267606999, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 20400964, 22451500, 22538716, 27328445, 37762649). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6825). 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: 20400964, 22167183, 24141787, 25292178, 26354865). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Benign

0.92

DEOGEN2

Benign

0.077

T;T;T;T;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.82

LIST_S2

Pathogenic

1.0

D;D;D;D;D

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.77

D;D;D;D;D

MetaSVM

Benign

-0.54

MutationAssessor

Pathogenic

3.7

.;.;H;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.6

.;.;D;D;.

REVEL

Uncertain

0.59

Sift

Uncertain

0.0030

.;.;D;D;.

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

0.99

.;.;D;.;.

Vest4

0.90, 0.89

MutPred

0.92

.;Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);.;.;

MVP

0.84

MPC

0.87

ClinPred

0.97

GERP RS

2.6

Varity_R

0.76

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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