chr17-58734181-A-G

Variant names:

• chr17-58734181-A-G
• rs587782565
• NM_058216.3:c.1090A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_058216.3(RAD51C):​c.1090A>G​(p.Ser364Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,461,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. S364N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:2
• Conservation: PhyloP100: 2.20
• Publications: 3 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0711073).

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.1090A>G	p.Ser364Gly	missense	Exon 9 of 9	NP_478123.1
	RAD51C	NR_103872.2		n.965A>G		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.1090A>G	p.Ser364Gly	missense	Exon 9 of 9	ENSP00000336701.4
	RAD51C	ENST00000482007.5	TSL:1	n.*518A>G		non_coding_transcript_exon	Exon 8 of 8	ENSP00000433332.1
	RAD51C	ENST00000482007.5	TSL:1	n.*518A>G		3_prime_UTR	Exon 8 of 8	ENSP00000433332.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250248 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461212 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 726816

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111668

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000564 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Apr 15, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting, BS3_Supporting, BP4_Moderate c.1090A>G, located in exon 9 of the RAD51C gene, is predicted to result in the substitution of Serine by Glycine at codon 364, p.(Ser364Gly). This variant is found in 2/267226 alleles at a frequency of 0.0007% in the gnomAD v2.1.1 database, non-cancer dataset (PM2_Supporting). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0,118) suggests that it does not affect the protein function according Pejaver 2022 thresholds (PMID: 36413997) (BP4_Moderate). A homology-directed repair (HDR) assay in reconstituted RAD51C-/- CL-V4B cells showed that c.1090A>G; p.(Ser364Gly) variant retains high levels of RAD51C protein activitiy (PMID: 37253112)(BS3_Supporting). The c.1090A>G variant has been identified in a proband from a cohort of 146 high-risk breast cancer families (PMID: 22476429). Additionally, it has been found in germline control DNA from a case-control study including 3,429 patients with invasive epithelial ovarian cancer, 2,772 controls, and 2,000 unaffected women who were BRCA1/BRCA2-negative (PMID: 26261251). This variant has been reported in the ClinVar database (6x uncertain significance, 1x likely pathogenic) and in the LOVD database (2x NA, 1x uncertain significance). At present ClinVar does not describe pathogenic or likely pathogenic missense variants in this codon. Based on the currently available information, c.1090A>G is classified as likely benign according to ACMG guidelines.

May 08, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with glycine at codon 364 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function . To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 22476429) and also detected in a female unaffected with cancer at age 70 and older (https://whi.color.com/variant/17-56811542-A-G). This variant has been reported in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51C_000228), and in an ovarian cancer case-control study in 1/2772 unaffected individuals and absent in 3429 cases (PMID: 26261251). This variant has been identified in 2/281650 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.

Mar 05, 2025

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Premature ovarian failure Pathogenic:1

Mar 02, 2020

Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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

Mar 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Jun 10, 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 indicates that this missense variant does not alter protein structure/function; Observed in an individual with a personal history of breast cancer and a family history of breast and/or ovarian cancer (PMID: 22476429); Published functional studies demonstrate normal in vitro homology-directed repair (HDR) activity (PMID: 37253112); This variant is associated with the following publications: (PMID: 34480478, 26261251, 25470109, 26406419, 23117857, 34923718, 14704354, 22476429, 37253112)

Familial ovarian cancer Uncertain:1

Feb 15, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia complementation group O Uncertain:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 364 of the RAD51C protein (p.Ser364Gly). This variant is present in population databases (rs587782565, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 22476429, 26261251). ClinVar contains an entry for this variant (Variation ID: 142585). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect RAD51C function (PMID: 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.

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

Aug 30, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Benign	0.77
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.2
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.12
Sift	Benign	0.037	D
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.064
MutPred		0.14		Loss of phosphorylation at S364 (P = 0.0112)
MVP		0.66
MPC		0.21
ClinPred		0.082	T
GERP RS		3.9
Varity_R		0.055
gMVP		0.15
Mutation Taster		=91/9	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587782565; hg19: chr17-56811542;