rs35151472

Positions:

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

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]

RAD51C links:

RAD51C (HGNC:):

RAD51C links:

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
RAD51C	NM_058216.3 linkuse as main transcript	c.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
RAD51C	ENST00000337432.9 linkuse as main transcript	c.485G>A	p.Gly162Glu	missense_variant	3/9	1	NM_058216.3	ENSP00000336701.4		O43502-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251482

Hom.:

AF XY:

0.00000736

AC XY:

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:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

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.:

Alfa

AF:

0.0000386

Hom.:

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

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2024	Identified 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 submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 08, 2017	- -
Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 25, 2011	Curator: Arleen D. Auerbach. Submitter to LOVD: Ian Campbell. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 19, 2021	This 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 05, 2024	The 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. -

Breast-ovarian cancer, familial, susceptibility to, 3

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 07, 2024

This 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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

This 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

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

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

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Uncertain

-0.15

MutationAssessor

Pathogenic

4.1

.;.;H;.;.

PrimateAI

Uncertain

0.74

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over