rs730881942

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_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 (★★). Synonymous variant affecting the same amino acid position (i.e. G31G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: -1.36

Publications

11 publications found

Variant links:

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]

RAD51C Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 3
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
Fanconi anemia complementation group O
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RAD51C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 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 267 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 182847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3 link	c.93delG	p.Phe32SerfsTer8	frameshift_variant	Exon 1 of 9	ENST00000337432.9	NP_478123.1	O43502-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9 link	c.93delG	p.Phe32SerfsTer8	frameshift_variant	Exon 1 of 9	1	NM_058216.3	ENSP00000336701.4		O43502-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000477

AC:

AN:

251464

AF XY:

0.0000589

show subpopulations

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 FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1112004

Other (OTH)

AF:

0.000132

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41584

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 3

Pathogenic:4Other:1

Aug 26, 2022

BRCAlab, Lund University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 15, 2011

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 27, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Nov 26, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Jan 27, 2022

Sema4, Sema4

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Apr 22, 2025

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. -

Apr 09, 2024

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 individuals affected with breast cancer and/or ovarian cancer with family history of cancer (PMID: 21616938, 37563628). 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. -

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:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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 -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Mar 05, 2025

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RAD51C c.93delG (p.Phe32SerfsX8) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 5.5e-05 in 255636 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RAD51C causing Hereditary Breast And Ovarian Cancer Syndrome (5.5e-05 vs 6.3e-05), allowing no conclusion about variant significance. 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)). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26681312, 21616938, 26556299, 27433846). ClinVar contains an entry for this variant (Variation ID: 182847). Based on the evidence outlined above, the variant was classified as pathogenic. -

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.4

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over