rs1555605532

chr17-58734130-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_058216.3(RAD51C):c.1039A>T(p.Arg347Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51C NM_058216.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 1.27

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 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0813 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-58734130-A-T is Pathogenic according to our data. Variant chr17-58734130-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449729.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3	c.1039A>T	p.Arg347Ter	stop_gained	9/9	ENST00000337432.9
LOC105371843	XR_007065866.1	n.81-9705T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9	c.1039A>T	p.Arg347Ter	stop_gained	9/9	1	NM_058216.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 26, 2020	This variant changes 1 nucleotide in exon 9 of the RAD51C gene, creating a translation stop signal. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein lacking the functionally important nuclear localization signal (a.a. 366-370) required for nuclear localization and robust rescue of sensitivity to mitomycin C treatment in RAD51-deficient cells (PMID: 12966089). To our knowledge, functional studies have not been reported for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. However, splice site and deletion variants that disrupt the last exon 9, encoding a.a. 343-376, have been reported in individuals affected with ovarian cancer (PMID: 26270727, Color internal data, communication with external laboratory). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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 10, 2023	The p.R347* variant (also known as c.1039A>T), located in coding exon 9 of the RAD51C gene, results from an A to T substitution at nucleotide position 1039. This changes the amino acid from an arginine to a stop codon within coding exon 9. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of RAD51C, and is not expected to trigger nonsense-mediated mRNA decay. This alteration impacts only the last 30 amino acids of the protein, including a nuclear localization signal (French CA et al. J. Biol. Chem, 2003 Nov;278(46):45445-50). The exact functional impact of these removed amino acids is currently unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 17, 2020

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 30 amino acids are lost including the nuclear localization signal (French 2003); Not observed in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge -

Fanconi anemia complementation group O Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the nuclear localization signal (NLS) of the RAD51C protein, which is important for proper localization and function of the RAD51C protein (PMID:12966089). While functional studies have not been performed to directly test the effect of this variant on RAD51C protein function, this suggests that disruption of this region of the protein is causative of disease. ClinVar contains an entry for this variant (Variation ID: 449729). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg347*) in the RAD51C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the RAD51C protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.28
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.30	T
MetaRNN	Pathogenic	0.86	D
MutationTaster	Benign	1.0	D
MVP		0.72
GERP RS		1.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555605532; hg19: chr17-56811491;