rs765730332

Variant names:

• chr17-58696746-G-A
• rs765730332
• NM_058216.3:c.458G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-58696746-G-A
• chr17-58696746-G-C
• chr17-58696746-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_058216.3(RAD51C):​c.458G>A​(p.Gly153Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,872 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).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:8
• Conservation: PhyloP100: 6.94

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.458G>A	p.Gly153Asp	missense_variant	Exon 3 of 9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.458G>A	p.Gly153Asp	missense_variant	Exon 3 of 9	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251462 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135908

Gnomad AFR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:2

Apr 05, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25470109, 36969410, 28829762, 36099300, 14704354, 37253112, 32322110, 23117857, 21980511) -

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. -

Nov 15, 2017

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 28, 2016

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.458G>A (p.Gly153Asp) in RAD51C gene is a missense change that involves a conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant is located outside of any known functional domain. Yet, functional studies have shown that this missense change alters the ability of RAD51C protein to form a complex with XRCC1 and RAD51B. (Clague, 2011). The variant is present in the large control population dataset of ExAC at a low frequency 0.000008 (1/121372 chrs tested), which does not exceed the maximal expected frequency of a pathogenic allele (0.00006) in this gene. The variant has been reported in at least 1 affected individuals in the literature without segregation analysis being performed. In addition, several reputable databases/clinical laboratories classify the variant as VUS. Lastly, this variant was identified in an internal specimen undergoing genetic testing together with c.1100delC in CHEK2 gene. Taken together, the variant was classified as VUS until more data become available. -

Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:1 Uncertain: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]. -

Oct 10, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2

Nov 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G153D variant (also known as c.458G>A), located in coding exon 3 of the RAD51C gene, results from a G to A substitution at nucleotide position 458. The glycine at codon 153 is replaced by aspartic acid, an amino acid with similar properties. This alteration has previously been reported in an individual diagnosed with breast cancer at age 60 and ovarian cancer at age 79. Functional analyses of this alteration showed little effect on RAD51C protein expression (immunoblot assay); however, it disrupted the interaction between RAD51C and RAD51B and XRCC3 in yeast two-hybrid assays (Clague J, PLoS ONE 2011 ; 6(9):e25632). In multiple assays testing RAD51C function, this alteration showed a abnormal read-out (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 available evidence, the clinical significance of this variant remains unclear. -

Apr 03, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Dec 19, 2022

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the RAD51C gene demonstrated a sequence change, c.458G>A, in exon 3 that results in an amino acid change, p.Gly153Asp. This sequence change has been previously described in an individual with breast and ovarian cancer (PMID: 21980511). Functional assays showed that this variant alters the ability of RAD51C to interact with XRCC3 and RAD51B but no significant impact on RAD51C protein expression (PMID: 21980511). This sequence change has been described in the gnomAD database in two individuals which corresponds to a population frequency of 0.0008% (dbSNP rs765730332). The p.Gly153Asp change affects a highly conserved amino acid residue located in a domain of the RAD51C protein that is known to be functional. The p.Gly153Asp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences the clinical significance of the p.Gly153Asp change remains unknown at this time. -

Fanconi anemia complementation group O Uncertain:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 153 of the RAD51C protein (p.Gly153Asp). This variant is present in population databases (rs765730332, gnomAD 0.003%). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 21980511). ClinVar contains an entry for this variant (Variation ID: 185444). 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: 21980511, 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	0.88
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T;T;T;T;T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Uncertain	0.067	D
MutationAssessor	Pathogenic	3.3	.;.;M;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.3	.;.;D;D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	.;.;D;D;.
Sift4G	Uncertain	0.013	D;D;D;D;D
Polyphen		1.0	.;.;D;.;.
Vest4		0.91, 0.90
MutPred		0.83		.;Gain of catalytic residue at G153 (P = 0.054);Gain of catalytic residue at G153 (P = 0.054);.;.;
MVP		0.93
MPC		0.96
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs765730332; hg19: chr17-56774107;