Variant chr17-58734152-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_058216.3(RAD51C):c.1061C>T(p.Ala354Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,461,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.466

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08180496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3 linkuse as main transcript	c.1061C>T	p.Ala354Val	missense_variant	9/9	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.1061C>T	p.Ala354Val	missense_variant	9/9	1	NM_058216.3	ENSP00000336701.4		O43502-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250548

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135368

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1461352

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000306

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 03, 2023	This missense variant replaces alanine with valine at codon 354 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID 26261251). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 3/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51C_000223). This variant has been identified in 2/250548 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	Jul 17, 2023	The p.A354V variant (also known as c.1061C>T), located in coding exon 9 of the RAD51C gene, results from a C to T substitution at nucleotide position 1061. The alanine at codon 354 is replaced by valine, an amino acid with similar properties. This alteration has been observed in one individual diagnosed with epithelial ovarian cancer (Song H et al. J. Clin. Oncol., 2015 Sep;33:2901-7). This variant was also reported in 3/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is 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 this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 05, 2022	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 03, 2018

This variant is denoted RAD51C c.1061C>T at the cDNA level, p.Ala354Val (A354V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant was observed in a patient with epithelial ovarian cancer (Song 2015). RAD51C Ala354Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with RAD51B, RAD51D, and XRCC3 (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether RAD51C Ala354Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Fanconi anemia complementation group O

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 354 of the RAD51C protein (p.Ala354Val). This variant is present in population databases (rs761770500, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 185785). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.083

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.62

M_CAP

Benign

0.0078

MetaRNN

Benign

0.082

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.60

REVEL

Benign

0.035

Sift

Benign

0.22

Sift4G

Benign

0.18

Polyphen

0.0030

Vest4

0.10

MutPred

0.20

Gain of sheet (P = 0.0344);

MVP

0.65

MPC

0.23

ClinPred

0.055

GERP RS

0.23

Varity_R

0.039

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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

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