rs730881925

Positions:

Variant summary

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

The ENST00000337432.9(RAD51C):c.746G>A(p.Arg249His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,458,812 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R249C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RAD51C
ENST00000337432.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 7.47

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, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3 linkuse as main transcript	c.746G>A	p.Arg249His	missense_variant	5/9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9 linkuse as main transcript	c.746G>A	p.Arg249His	missense_variant	5/9	1	NM_058216.3	ENSP00000336701	P2	O43502-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151796

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251434

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

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:

0.000163

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1458812

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

725940

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

151796

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74090

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000487

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 3

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Nov 22, 2019	This variant has been reported in the literature in an individual with breast cancer (Lu 2015). This variant has an overall allele frequency of 0.000016 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.746G>A (p.Arg249His) has been reported in an individual with breast cancer, as well as an unaffected control individual (Lu C et al., 2015). This missense variant has been submitted to ClinVar as a Variant of Uncertain Significance. The p.Arg249His variant is is observed in 0.001% alleles in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Arg at position 249 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg249His in RAD51C is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 04, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 10, 2022	This missense variant replaces arginine with histidine at codon 249 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 observed in an individual affected with breast cancer (PMID: 26689913) and in a control individual from an ovarian cancer case-control study (PMID: 26261251). In a large breast cancer case-control study, this variant was observed in 1/60466 cases and 2/53461 unaffected controls (OR=0.442, 95%CI 0.04 to 4.876, p-value=0.603) (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51C_000187). This variant has also been identified in 5/251434 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2022	The p.R249H variant (also known as c.746G>A), located in coding exon 5 of the RAD51C gene, results from a G to A substitution at nucleotide position 746. The arginine at codon 249 is replaced by histidine, an amino acid with highly similar properties. In one study, this variant was not observed in 3429 patients with invasive epithelial ovarian cancer, but was reported in 1/2722 controls (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). This variant has also been reported in a patient with breast cancer (Lu C et al. Nat. Commun. 2015 Dec;6:10086). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 23, 2018

Variant summary: RAD51C c.746G>A (p.Arg249His) results in a non-conservative amino acid change located in the C-terminal of the Rad51-like DNA recombination and repair protein domain and the RecA-like DNA recombination and repair protein ATP-binding domain. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 2e-05 in 255756 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in RAD51C causing Hereditary Breast and Ovarian Cancer (2e-05 vs 6.3e-05), allowing no conclusion about variant significance. The variant, c.746G>A, has been reported in the literature in a cohort of cancer cases (specific phenotype not provided; Lu_2015). This report does not provide an unequivocal conclusion about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 07, 2018

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 27, 2024

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; Published functional studies demonstrate no damaging effect on RAD51D, RAD51B, and XRCC3 interactions (PMID: 36099300); This variant is associated with the following publications: (PMID: 26261251, 33471991, 26689913, 14704354, 25085752, 36099300) -

Fanconi anemia complementation group O

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 249 of the RAD51C protein (p.Arg249His). This variant is present in population databases (rs730881925, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 26261251, 26689913). ClinVar contains an entry for this variant (Variation ID: 182828). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAD51C protein function. 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

0.57

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

T;T;T;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.81

D;D;D;D

MetaSVM

Uncertain

-0.087

MutationAssessor

Pathogenic

3.6

.;.;H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.2

.;.;D;.

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

.;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.97

.;.;D;.

Vest4

0.82, 0.82

MutPred

0.57

.;Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);.;

MVP

0.84

MPC

0.80

ClinPred

1.0

GERP RS

6.0

Varity_R

0.83

gMVP

0.75

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