17-58724069-C-T

Variant names:

• chr17-58724069-C-T
• rs730881932
• NM_058216.3:c.934C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM5 PP3_Strong PP5

The NM_058216.3(RAD51C):​c.934C>T​(p.Arg312Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,960 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. R312G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:3
• Conservation: PhyloP100: 0.925
• Publications: 13 publications found

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

LOC105371843 (HGNC:):

ACMG classification

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

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-58724069-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 665797.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 17-58724069-C-T is Pathogenic according to our data. Variant chr17-58724069-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 182836.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058216.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	NM_058216.3	MANE Select	c.934C>T	p.Arg312Trp	missense	Exon 7 of 9	NP_478123.1
	RAD51C	NR_103872.2		n.809C>T		non_coding_transcript_exon	Exon 6 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.934C>T	p.Arg312Trp	missense	Exon 7 of 9	ENSP00000336701.4
	RAD51C	ENST00000482007.5	TSL:1	n.*362C>T		non_coding_transcript_exon	Exon 6 of 8	ENSP00000433332.1
	RAD51C	ENST00000482007.5	TSL:1	n.*362C>T		3_prime_UTR	Exon 6 of 8	ENSP00000433332.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251360 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460960 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726838

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111226

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:3

Jan 03, 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: 28829762].

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 10, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RAD51C: PS3:Moderate, PS4:Moderate, PP1, PP3

Sep 12, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 28829762, 32957588, 34606182, 33471991, 35534704, 36099300, 38219492); 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: 28829762, 32957588, 14704354, 33471991, 37344589, 37253112, 34606182, 36099300, 35534704, 36243179, 38219492)

Hereditary breast ovarian cancer syndrome Pathogenic:2

Jul 16, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RAD51C c.934C>T (p.Arg312Trp) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-06 in 252652 control chromosomes. c.934C>T has been reported in the literature in individuals affected with breast cancer, ovarian cancer and colon cancer (Gayarre_2017, Germani_2020, de Oliveira_2022). Specifically, Gayarre_2017 identified the variant in two siblings with personal history of ovarian cancer and determined through segregation analysis that the variant was inherited from their mother (obligate carrier) who also was affected with ovarian cancer. These data indicate that the variant is likely to be associated with disease. Multiple publication report experimental evidence evaluating an impact on protein function. The variant protein was unable to complement RAD51C-deficient cells (Gayarre_2017) and was defective in a homology-directed DNA repair assay (Hu_2023). The following publications have been ascertained in the context of this evaluation (PMID: 28829762, 32957588, 37253112, 35534704). ClinVar contains an entry for this variant (Variation ID: 182836). Based on the evidence outlined above, the variant was classified as pathogenic.

Apr 18, 2025

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant NM_058216.3(RAD51C):c.934C>T (p.Arg312Trp) causes the same amino acid change as a previously established pathogenic variant. There is a moderate physicochemical difference between arginine and tryptophan. 3 variants within 6 amino acid positions of the variant p.Arg312Trp have been shown to be pathogenic, while none have been shown to be benign. For these reasons, this variant has been classified as Likely Pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Jun 24, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 312 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have shown that the mutant protein is defective in a homology-directed DNA repair assay (PMID: 37253112), in complementation of RAD51C-deficient cells and in interactions with RAD51D (PMID: 28829762, 36099300). This variant has been identified in individuals affected with ovarian cancer (PMID: 28829762, 36099300; DOI: 10.21203/rs.3.rs-1241858/v1) and in four individuals affected with breast cancer (PMID: 33471991, 34606182). This variant has been identified in 2/251360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Mar 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R312W variant (also known as c.934C>T), located in coding exon 7 of the RAD51C gene, results from a C to T substitution at nucleotide position 934. The arginine at codon 312 is replaced by tryptophan, an amino acid with dissimilar properties. In multiple assays testing RAD51C function, this variant showed functionally abnormal results (Gayarre J et al. Br J Cancer, 2017 Sep;117:1048-1062; Prakash R et al. Proc Natl Acad Sci U S A, 2022 Sep;119:e2202727119; Rawal Y et al. Nature, 2023 Jul;619:640-649; 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1

Jun 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia complementation group O Uncertain:1

Jun 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 312 of the RAD51C protein (p.Arg312Trp). This variant is present in population databases (rs730881932, gnomAD 0.006%). This missense change has been observed in individual(s) with ovarian and breast cancer (PMID: 28829762, 32957588, 35534704, 36243179). ClinVar contains an entry for this variant (Variation ID: 182836). 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) performed at Invitae 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: 28829762, 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		0.93
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.81		Gain of catalytic residue at R312 (P = 0.0367)
MVP		0.86
MPC		0.86
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.91
gMVP		0.90
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs730881932; hg19: chr17-56801430; COSMIC: COSV61675832;