chr17-58696802-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_058216.3(RAD51C):​c.514C>G​(p.Leu172Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L172F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RAD51C
NM_058216.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.26

Publications

1 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_058216.3
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.25196347).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAD51CNM_058216.3 linkc.514C>G p.Leu172Val 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.514C>G p.Leu172Val missense_variant Exon 3 of 9 1 NM_058216.3 ENSP00000336701.4 O43502-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251462
AF XY:
0.00000736
show subpopulations
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Sep 04, 2015
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.L172V variant (also known as c.514C>G), located in coding exon 3 of the RAD51C gene, results from a C to G substitution at nucleotide position 514. The leucine at codon 172 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 65000 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.L172V remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
15
DANN
Uncertain
0.97
DEOGEN2
Benign
0.0086
T;T;T;T;T
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.26
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.77
T;T;T;T;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.25
T;T;T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
1.3
.;.;L;.;.
PhyloP100
2.3
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.10
.;.;N;N;.
REVEL
Benign
0.051
Sift
Benign
0.17
.;.;T;T;.
Sift4G
Benign
0.14
T;T;T;T;T
Polyphen
0.0050
.;.;B;.;.
Vest4
0.42, 0.39
MutPred
0.64
.;Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);.;.;
MVP
0.81
MPC
0.24
ClinPred
0.14
T
GERP RS
-0.48
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.091
gMVP
0.63
Mutation Taster
=91/9
polymorphism

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

Other links and lift over

dbSNP: rs876660732; hg19: chr17-56774163; COSMIC: COSV99541511; COSMIC: COSV99541511; API