rs730881942

Variant names:

• chr17-58692732-CG-C
• rs730881942
• NM_058216.3:c.93delG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_058216.3(RAD51C):​c.93delG​(p.Phe32SerfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,200 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: RAD51C NM_058216.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: -1.36

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
• PP5: Variant 17-58692732-CG-C is Pathogenic according to our data. Variant chr17-58692732-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58692732-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.93delG	p.Phe32SerfsTer8	frameshift_variant	Exon 1 of 9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.93delG	p.Phe32SerfsTer8	frameshift_variant	Exon 1 of 9	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251464 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135912

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: 0.000185

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 727236

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: 0.000206

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:3 Other:1

Aug 15, 2011

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 05, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 26, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Mar 31, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.93delG pathogenic mutation, located in coding exon 1 of the RAD51C gene, results from a deletion of one nucleotide at position 93, causing a translational frameshift with a predicted alternate stop codon (p.F32Sfs*8). This mutation has been identified in a Finnish breast/ovarian cancer kindred as well as multiple ovarian cancer only families to date (Pelttari LM et al. Hum. Mol. Genet. 2011 Aug;20:3278-88). This same group did not find the c.93delG alteration in a group of 1083 prostate cancer patients and 802 colorectal cancer patients, leading the authors to conclude that this mutation does not predispose to prostate or colorectal cancer (Pelttari LM et al. BMC Cancer. 2012;12:552). In a different prostate cancer cohort, this alteration was identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). In addition, this alteration was identified in 2/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 08;18:823-32). 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. -

Feb 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 1 nucleotide in exon 1 of the RAD51C gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with familial ovarian cancer and another individual affected breast cancer with multiple relatives affected with breast or ovarian cancer (PMID: 21616938). This variant has also been observed in an individual with prostate cancer (PMID: 27433846). This variant has been identified in 13/282860 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Jan 27, 2022

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Pathogenic:2

May 01, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; This variant is associated with the following publications: (PMID: 23176254, 27806231, 25470109, 28152038, 21616938, 23117857, 24800917, 27433846, 26681312, 28874143, 28802053, 26556299, 26689913, 32107557, 34923718, 35053526, 35626031, 29922827, 28888541) -

Dec 09, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RAD51C c.93del (p.Phe32Serfs*8) variant alters the translational reading frame of the RAD51C mRNA and causes the premature termination of RAD51C protein synthesis. This variant has been reported in the published literature in individuals affected with prostate cancer (PMID: 27433846 (2016)), or breast and/or ovarian cancer (PMIDs: 24800917 (2014), 21616938 (2011)). The frequency of this variant in the general population, 0.000004 (1/251464 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

not specified Pathogenic:1

Apr 07, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RAD51C c.93delG; p.Phe32fs variant (rs730881942) is reported in the literature in individuals with breast and/or ovarian cancer, prostate cancer, soft tissue sarcoma, or hematologic cancer (Pelttari 2011, Pritchard 2016, Schrader 2016, Susswein 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 182847). It is found in the general population with an overall allele frequency of 0.005% (13/282860 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Pelttari LM et al. RAD51C is a susceptibility gene for ovarian cancer. Hum Mol Genet. 2011 Aug 15;20(16):3278-88. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Schrader KA et al. Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. JAMA Oncol. 2016 Jan;2(1):104-11. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. -

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

Jun 02, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inherited ovarian cancer (without breast cancer) Pathogenic:1

Sep 30, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1,PM5_Supporting -

Ovarian neoplasm Pathogenic:1

Feb 28, 2020

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. -

Fanconi anemia complementation group O Pathogenic:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Phe32Serfs*8) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer, prostate cancer (PMID: 21616938, 27433846). It is commonly reported in individuals of Finnish ancestry (PMID: 21616938, 24800917, 27433846). ClinVar contains an entry for this variant (Variation ID: 182847). For these reasons, this variant has been classified as Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Nov 22, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The RAD51C c.93delG (p.Phe32SerfsX8) variant results in a premature termination codon, predicted to cause a truncated or absent RAD51C protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 15/250416 control chromosomes at a frequency of 0.0000599, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). This variant has also been reported in multiple families and individuals with breast and/or ovarian cancer and based on haplotype analysis authors concluded that it is likely a founder mutation in the Finnish population that is associated with moderate-to-high risk susceptibility for ovarian cancer (Pelttari 2011). The founder effect can also explain the higher occurrence of the variant in this population (gnomAD 5/22298 Finnish European). The variant was also found in a patient with ovarian cancer in a different population (Susswein 2016). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.97C>T (p.Gln33X), c.397C>T (p.Gln133X), c.577C>T (p.Arg193X)). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs730881942; hg19: chr17-56770093;