17-58696780-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_058216.3(RAD51C):​c.492T>G​(p.Phe164Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,210 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: š‘“ 0.000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.000015 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

3
8
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15B:1

Conservation

PhyloP100: 2.11
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAD51CNM_058216.3 linkc.492T>G p.Phe164Leu 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
RAD51CENST00000337432.9 linkc.492T>G p.Phe164Leu missense_variant Exon 3 of 9 1 NM_058216.3 ENSP00000336701.4 O43502-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152218
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000524
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251476
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000260
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:
0.0000150
AC:
22
AN:
1461874
Hom.:
0
Cov.:
32
AF XY:
0.0000124
AC XY:
9
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000358
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:
0.00000270
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000656
AC:
10
AN:
152336
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000756
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:15Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:4
Jul 24, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.F164L variant (also known as c.492T>G), located in coding exon 3 of the RAD51C gene, results from a T to G substitution at nucleotide position 492. The phenylalanine at codon 164 is replaced by leucine, an amino acid with highly similar properties. This variant was identified in a cohort of 85 patients undergoing HBOC testing in Colombia (Cock-Rada AM et al. Fam. Cancer, 2018 01;17:23-30). This variant was also identified in an individual diagnosed with breast cancer (Weitzel JN et al. Cancer, 2019 08;125:2829-2836). This variant was reported in 2/60,466 breast cancer cases and in 3/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Oct 19, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Jan 07, 2025
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces phenylalanine with leucine at codon 164 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer, and one of them carried a pathogenic BRCA1 variant (PMID: 28528518; Vazquez-Juarez et al, poster P3-07-07, SABCS 2021). In an international breast cancer case-control meta-analysis, this variant was detected in 2/60466 cases and 3/53461 unaffected controls (PMID: 33471991). This variant has been identified in 10/251476 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. -

Jan 29, 2025
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

c.492T>G, located in exon 3 of the RAD51C gene, is predicted to result in the substitution of phenilalanine by leucine at codon 164, p.(Phe164Leu). This variant is found in 10/268291 alleles at a frequency of 0.003% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score (0.575) for this variant is indeterminate regarding the effect that it may have on protein function according to Pejaver 2022 thresholds (PMID: 36413997). To our knowledge, neither relevant clinical data nor well-established functional studies have been reported for this variant. This variant has been reported in hereditary cancer-suspected patients (PMID: 31921681, 30256826, 28528518) and has been assessed in case-control studies, where it has been found in both cases and controls, irrespective of the disease (PMID: 33471991, 31206626). This variant has been reported in the ClinVar database (1x likely benign, 13x uncertain significance) and has not been classified d in LOVD. Based on currently available information, the variant c.492T>G should be considered an uncertain significance variant according to ACMG/AMP classification guidelines. -

Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:3Benign:1
Mar 30, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 27, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 05, 2023
Myriad Genetics, Inc.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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]. -

Nov 02, 2016
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Fanconi anemia complementation group O Uncertain:3
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 164 of the RAD51C protein (p.Phe164Leu). This variant is present in population databases (rs573992101, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 28528518, 35534704). ClinVar contains an entry for this variant (Variation ID: 188317). 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 not expected to disrupt RAD51C protein function with a negative predictive value of 80%. 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. -

Jun 22, 2020
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Nov 02, 2016
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:2
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 27, 2025
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: RAD51C c.492T>G (p.Phe164Leu) results in a non-conservative amino acid change located in the ATP-binding domain (IPR020588) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251476 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RAD51C causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.492T>G, has been reported in the literature in individuals with personal and/or family history of breast and/or ovarian cancer, and other tumor phenotypes (e.g. Cock-Rada_2018, Martin-Morales_2018, Weitzel_2019, Oliver_2019), however it was also found in controls (e.g. Weitzel_2019 and in the FLOSSIES database). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.1674delA, p.Gly559ValfsX13). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28528518, 30256826, 31206626, 31921681, 33471991). ClinVar contains an entry for this variant (Variation ID: 188317). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:2
Jun 21, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The RAD51C c.492T>G (p.Phe164Leu) variant has been reported in the published literature in individuals with breast cancer (PMID: 28528518 (2017), 31206626 (2019), 35534704 (2022)) and colorectal cancer (PMID: 30256826 (2018)). In a large-scale breast cancer association study, this variant was observed in individuals with breast cancer as well as in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51C)). The frequency of this variant in the general population, 0.00026 (9/34592 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Feb 02, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Observed in individuals meeting clinical criteria for Lynch syndrome or hereditary breast and ovarian cancer syndrome, as well as in both cases and controls in breast cancer studies (PMID: 28528518, 33471991, 30256826, 31921681, 31206626, 35534704, 37842866); 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: 30256826, 28528518, 31921681, 31206626, 14704354, 35534704, 33471991, 37842866, Vzquez2021) -

Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1
Mar 20, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Uncertain
0.042
T
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.097
T;T;T;T;T
Eigen
Benign
-0.018
Eigen_PC
Benign
0.064
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.94
D;D;D;D;D
M_CAP
Benign
0.024
T
MetaRNN
Pathogenic
0.86
D;D;D;D;D
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
2.0
.;.;M;.;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-5.2
.;.;D;D;.
REVEL
Uncertain
0.57
Sift
Benign
0.037
.;.;D;D;.
Sift4G
Uncertain
0.058
T;D;D;T;T
Polyphen
1.0
.;.;D;.;.
Vest4
0.89, 0.90
MutPred
0.90
.;Loss of stability (P = 0.0985);Loss of stability (P = 0.0985);.;.;
MVP
0.82
MPC
0.88
ClinPred
0.88
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.60
gMVP
0.90

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs573992101; hg19: chr17-56774141; API