rs35151472

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_058216.3(RAD51C):​c.485G>A​(p.Gly162Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,864 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: 0.0000034 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

7
9
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5

Conservation

PhyloP100: 8.84
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 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.898
PP5
Variant 17-58696773-G-A is Pathogenic according to our data. Variant chr17-58696773-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220285.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAD51CNM_058216.3 linkuse as main transcriptc.485G>A p.Gly162Glu missense_variant 3/9 ENST00000337432.9 NP_478123.1 O43502-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAD51CENST00000337432.9 linkuse as main transcriptc.485G>A p.Gly162Glu missense_variant 3/91 NM_058216.3 ENSP00000336701.4 O43502-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251482
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135914
show subpopulations
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 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:
0.00000342
AC:
5
AN:
1461864
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:2
Uncertain significance, no assertion criteria providedcurationLeiden Open Variation DatabaseAug 25, 2011Curator: Arleen D. Auerbach. Submitter to LOVD: Ian Campbell. -
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 21, 2024Identified in individuals with a personal and/or family history of breast and/or ovarian cancer for whom previous BRCA1/2 testing was negative (PMID: 21990120); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25470109, 25086635, 26261251, 23117857, 28829762, 21537932, 36099300, 21990120, 37253112, 14704354) -
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJun 08, 2017- -
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 05, 2024The p.G162E variant (also known as c.485G>A), located in coding exon 3 of the RAD51C gene, results from a G to A substitution at nucleotide position 485. The glycine at codon 162 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in the literature in individuals diagnosed with breast and/or ovarian cancer (Thompson ER et al. Hum. Mutat. 2012 Jan;33:95-9). This variant was identified in 0/3447 cases of invasive epithelial ovarian cancer and in 1/4812 unaffected controls (Song H et al. J Clin Oncol, 2015 Sep;33:2901-7). 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. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 19, 2021This missense variant replaces glycine with glutamic acid at codon 162 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 21990120). This variant has also been reported in a healthy control individual (PMID: 26261251). This variant has been identified in 1/251482 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. -
Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Feb 07, 2024This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 37253112, 36099300]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 11, 2024This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 162 of the RAD51C protein (p.Gly162Glu). This variant is present in population databases (rs35151472, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 21990120). ClinVar contains an entry for this variant (Variation ID: 220285). 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%. 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
0.86
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
T;T;T;T;T
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.95
D;D;D;D;D
M_CAP
Benign
0.025
T
MetaRNN
Pathogenic
0.90
D;D;D;D;D
MetaSVM
Uncertain
-0.15
T
MutationAssessor
Pathogenic
4.1
.;.;H;.;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-7.2
.;.;D;D;.
REVEL
Uncertain
0.59
Sift
Uncertain
0.0020
.;.;D;D;.
Sift4G
Uncertain
0.0050
D;D;D;D;D
Polyphen
1.0
.;.;D;.;.
Vest4
0.81, 0.79
MutPred
0.77
.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;
MVP
0.92
MPC
0.96
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.95
gMVP
0.88

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: rs35151472; hg19: chr17-56774134; API