17-58724091-G-C

Variant names:

• chr17-58724091-G-C
• rs367846829
• NM_058216.3:c.956G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_058216.3(RAD51C):​c.956G>C​(p.Arg319Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.197

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]

LOC105371843 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25494915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.956G>C	p.Arg319Pro	missense_variant	Exon 7 of 9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.956G>C	p.Arg319Pro	missense_variant	Exon 7 of 9	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Sep 17, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted RAD51C c.956G>C at the cDNA level, p.Arg319Pro (R319P) at the protein level, and results in the change of an Arginine to a Proline (CGA>CCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Arg319Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Arg319Pro occurs at a position that is poorly conserved across species, although it is expressed through monotremes, and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether RAD51C Arg319Pro is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R319P variant (also known as c.956G>C), located in coding exon 7 of the RAD51C gene, results from a G to C substitution at nucleotide position 956. The arginine at codon 319 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is conserved. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.0072	T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.29	.;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.54	.;N
REVEL	Benign	0.20
Sift	Benign	0.074	.;T
Sift4G	Benign	0.30	T;T
Polyphen		0.0	.;B
Vest4		0.46
MutPred		0.50		Loss of MoRF binding (P = 0.0013);Loss of MoRF binding (P = 0.0013);
MVP		0.65
MPC		0.33
ClinPred		0.11	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.44

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

Other links and lift over

dbSNP: rs367846829; hg19: chr17-56801452;