chr17-58724069-C-T

Position:

chr17-58724069-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_058216.3(RAD51C):c.934C>T(p.Arg312Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,960 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R312G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2

Conservation

PhyloP100: 0.925

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 5 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

PP5

Variant 17-58724069-C-T is Pathogenic according to our data. Variant chr17-58724069-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182836.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=5, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3 linkuse as main transcript	c.934C>T	p.Arg312Trp	missense_variant	7/9	ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9 linkuse as main transcript	c.934C>T	p.Arg312Trp	missense_variant	7/9	1	NM_058216.3	P2	O43502-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251360

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460960

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726838

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 3

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 03, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 28829762]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 10, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2024	The p.R312W variant (also known as c.934C>T), located in coding exon 7 of the RAD51C gene, results from a C to T substitution at nucleotide position 934. The arginine at codon 312 is replaced by tryptophan, an amino acid with dissimilar properties. In multiple assays testing RAD51C function, this variant showed functionally abnormal results (Gayarre J et al. Br J Cancer, 2017 Sep;117:1048-1062; Prakash R et al. Proc Natl Acad Sci U S A, 2022 Sep;119:e2202727119; Rawal Y et al. Nature, 2023 Jul;619:640-649; Hu C et al. Cancer Res, 2023 Aug;83:2557-2571). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 21, 2023	This missense variant replaces arginine with tryptophan at codon 312 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have shown that the mutant protein is defective in a homology-directed DNA repair assay (PMID: 37253112), in complementation of RAD51C-deficient cells and in interactions with RAD51D (PMID: 28829762, 36099300). This variant has been identified in individuals affected with ovarian cancer (PMID: 28829762, 36099300; DOI: 10.21203/rs.3.rs-1241858/v1) and in four individuals affected with breast cancer (PMID: 33471991, 34606182). This variant has been identified in 2/251360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 12, 2024

Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 28829762, 32957588, 34606182, 33471991, 35534704, 36099300, 38219492); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28829762, 32957588, 14704354, 33471991, 37344589, 37253112, 34606182, 36099300, 35534704, 36243179, 38219492) -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 16, 2024

Variant summary: RAD51C c.934C>T (p.Arg312Trp) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-06 in 252652 control chromosomes. c.934C>T has been reported in the literature in individuals affected with breast cancer, ovarian cancer and colon cancer (Gayarre_2017, Germani_2020, de Oliveira_2022). Specifically, Gayarre_2017 identified the variant in two siblings with personal history of ovarian cancer and determined through segregation analysis that the variant was inherited from their mother (obligate carrier) who also was affected with ovarian cancer. These data indicate that the variant is likely to be associated with disease. Multiple publication report experimental evidence evaluating an impact on protein function. The variant protein was unable to complement RAD51C-deficient cells (Gayarre_2017) and was defective in a homology-directed DNA repair assay (Hu_2023). The following publications have been ascertained in the context of this evaluation (PMID: 28829762, 32957588, 37253112, 35534704). ClinVar contains an entry for this variant (Variation ID: 182836). Based on the evidence outlined above, the variant was classified as pathogenic. -

Fanconi anemia complementation group O

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 20, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 312 of the RAD51C protein (p.Arg312Trp). This variant is present in population databases (rs730881932, gnomAD 0.006%). This missense change has been observed in individual(s) with ovarian and breast cancer (PMID: 28829762, 32957588, 36243179). ClinVar contains an entry for this variant (Variation ID: 182836). 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. Experimental studies have shown that this missense change affects RAD51C function (PMID: 28829762). 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

0.78

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

T;D

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Pathogenic

4.3

.;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.9

.;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.94

MutPred

0.81

Gain of catalytic residue at R312 (P = 0.0367);Gain of catalytic residue at R312 (P = 0.0367);

MVP

0.86

MPC

0.86

ClinPred

1.0

GERP RS

4.0

Varity_R

0.91

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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