rs754367349

chr17-58709926-GT-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_058216.3(RAD51C):c.774del(p.Thr259LeufsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,459,932 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R258R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RAD51C NM_058216.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: -0.549

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-58709926-GT-G is Pathogenic according to our data. Variant chr17-58709926-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 419188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58709926-GT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3	c.774del	p.Thr259LeufsTer4	frameshift_variant	5/9	ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9	c.774del	p.Thr259LeufsTer4	frameshift_variant	5/9	1	NM_058216.3	P2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251428 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135886

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: 0.0000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1459932 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 726444

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: 0.0000162

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jul 24, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2021	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal and family history of RAD51C-related cancers in published literature (Romero 2011, Vuorela 2011, Cunningham 2014, Song 2015, Nguyen-Dumont 2020); This variant is associated with the following publications: (PMID: 23117857, 26261251, 21616938, 25086635, 24800917, 21537932, 21750962, 22451500, 24504028, 21990120, 20400964, 32338768, 25470109) -

Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Sep 10, 2019	This variant leads to a translational frameshift and the introduction of a premature termination codon four residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of RAD51C is a well-established mechanism of disease for increased ovarian cancer risk [Romero 2011, Vuorela 2011, Song 2015]. This variant has been reported in individuals with breast and ovarian cancer [Meindl 2010, Thompson 2012, Rashid 2014]. This variant has a combined allele frequency of 0.000045 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 13, 2023	The c.774delT pathogenic mutation, located in coding exon 5 of the RAD51C gene, results from a deletion of one nucleotide at nucleotide position 774, causing a translational frameshift with a predicted alternate stop codon (p.T259Lfs*4). This mutation has been reported in multiple individuals with a personal and/or family history of breast and/or ovarian cancer and has also been proposed as a Swedish founder mutation (Romero A et al. Breast Cancer Res. Treat. 2011 Oct;129:939-46; Vuorela M et al. Breast Cancer Res. Treat. 2011 Dec;130:1003-10; Osorio A et al. Hum. Mol. Genet., 2012 Jul;21:2889-98; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 29, 2017	- -

Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 14, 2017

- -

Fanconi anemia complementation group O Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

This sequence change creates a premature translational stop signal (p.Thr259Leufs*4) in the RAD51C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917, 29278735). This variant is present in population databases (rs754367349, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 21537932, 21750962, 26261251). ClinVar contains an entry for this variant (Variation ID: 419188). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754367349; hg19: chr17-56787287;