17-58696836-T-C

Position:

chr17-58696836-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The ENST00000337432.9(RAD51C):c.548T>C(p.Ile183Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. I183V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

RAD51C
ENST00000337432.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in ENST00000337432.9

BP4

Computational evidence support a benign effect (MetaRNN=0.36996746).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3 linkuse as main transcript	c.548T>C	p.Ile183Thr	missense_variant	3/9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9 linkuse as main transcript	c.548T>C	p.Ile183Thr	missense_variant	3/9	1	NM_058216.3	ENSP00000336701	P2	O43502-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251468

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135906

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727228

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:

0.0000243

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 15, 2023	The p.I183T variant (also known as c.548T>C), located in coding exon 3 of the RAD51C gene, results from a T to C substitution at nucleotide position 548. The isoleucine at codon 183 is replaced by threonine, an amino acid with similar properties. In one study, this variant was seen in 1 of 1404 breast and/or ovarian cancer cases with family histories of breast and/or ovarian cancer and in 0 of 1156 population controls (Loveday C et al. Nat. Genet. 2012 Apr;44:475-6; author reply 476). In a homology-directed DNA repair (HDR) assay, this alteration showed a functionally normal read-out (Hu C et al. Cancer Res, 2023 Aug;83:2557-2571). 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2023	This missense variant replaces isoleucine with threonine at codon 183 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 reported for this variant. This variant has been observed in an individual affected with ovarian and/or breast cancer (PMID: 22538716). This variant has been identified in 2/251468 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. -

Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 27, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 2023

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; Observed in 1/2,808 ovarian cancer cases and was absent from 2,312 controls (Loveday et al., 2012); This variant is associated with the following publications: (PMID: 25470109, 22538716, 14704354) -

Fanconi anemia complementation group O

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 23, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 183 of the RAD51C protein (p.Ile183Thr). This variant is present in population databases (rs756727559, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 22538716). ClinVar contains an entry for this variant (Variation ID: 187692). 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. 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

Jul 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

T;T;T;T;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.77

T;T;T;T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.37

T;T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.3

.;.;M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.2

.;.;N;D;.

REVEL

Benign

0.18

Sift

Benign

0.10

.;.;T;T;.

Sift4G

Benign

0.20

T;T;T;D;D

Polyphen

0.74

.;.;P;.;.

Vest4

0.46, 0.54

MutPred

0.65

.;Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);.;.;

MVP

0.83

MPC

0.31

ClinPred

0.47

GERP RS

4.6

Varity_R

0.10

gMVP

0.49

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