17-58703291-G-T

Variant names:

• chr17-58703291-G-T
• NM_058216.3:c.667G>T

Variant summary

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

The NM_058216.3(RAD51C):​c.667G>T​(p.Val223Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.51

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.667G>T	p.Val223Phe	missense_variant	Exon 4 of 9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.667G>T	p.Val223Phe	missense_variant	Exon 4 of 9	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

May 14, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 29, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V223F variant (also known as c.667G>T), located in coding exon 4 of the RAD51C gene, results from a G to T substitution at nucleotide position 667. The valine at codon 223 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is not well 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. -

Jan 22, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting c.667G>T, located in exon 4 of the RAD51C gene, is predicted to result in the substitution of Val by Phe at codon 223, p.(Val223Phe). t is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing, but the REVEL meta-predictor score (0.44) for this variant is indeterminate regarding the effect that it may have on protein function according Pejaver 2022 thresholds (PMID: 36413997). To our knowledge, neither clinical data nor functional studies have been reported for this variant. It has only been reported twice in ClinVar, as an uncertain significance variant. Based on currently available information, the variant c.667G>T should be considered an uncertain significance variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T;T;T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.5	.;.;M;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.5	.;.;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0040	.;.;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.76	.;.;P;.
Vest4		0.83, 0.84
MutPred		0.59		.;Loss of stability (P = 0.1963);Loss of stability (P = 0.1963);.;
MVP		0.89
MPC		0.45
ClinPred		0.95	D
GERP RS		1.5
Varity_R		0.54
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-56780652;