5-132595759-TAA-TAAA

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_005732.4(RAD50):c.2165dupA(p.Glu723GlyfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,598,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

RAD50
NM_005732.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:1

Conservation

PhyloP100: -0.126

Publications

27 publications found

Variant links:

Genes affected

RAD50 (HGNC:9816): (RAD50 double strand break repair protein) The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Rad50, a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1. The protein complex binds to DNA and displays numerous enzymatic activities that are required for nonhomologous joining of DNA ends. This protein, cooperating with its partners, is important for DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance, and meiotic recombination. Knockout studies of the mouse homolog suggest this gene is essential for cell growth and viability. Mutations in this gene are the cause of Nijmegen breakage syndrome-like disorder.[provided by RefSeq, Apr 2010]

RAD50 Gene-Disease associations (from GenCC):

Nijmegen breakage syndrome-like disorder
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RAD50 links:

ENSG00000283782 (HGNC:):

ENSG00000283782 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 5-132595759-T-TA is Pathogenic according to our data. Variant chr5-132595759-T-TA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141045.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005732.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	NM_005732.4	MANE Select	c.2165dupA	p.Glu723GlyfsTer5	frameshift	Exon 13 of 25	NP_005723.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RAD50	ENST00000378823.8	TSL:1 MANE Select	c.2165dupA	p.Glu723GlyfsTer5	frameshift	Exon 13 of 25	ENSP00000368100.4
ENSG00000283782	ENST00000638452.2	TSL:5	c.1868dupA	p.Glu624GlyfsTer5	frameshift	Exon 15 of 27	ENSP00000492349.2
RAD50	ENST00000533482.5	TSL:1	n.*1791dupA		non_coding_transcript_exon	Exon 13 of 25	ENSP00000431225.1

Frequencies

GnomAD3 genomes

AF:

0.000140

AC:

AN:

150326

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000195

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000163

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000271

AC:

AN:

239710

AF XY:

0.000246

show subpopulations

Gnomad AFR exome

AF:

0.000192

Gnomad AMR exome

AF:

0.000242

Gnomad ASJ exome

AF:

0.000205

Gnomad EAS exome

AF:

0.000454

Gnomad FIN exome

AF:

0.000455

Gnomad NFE exome

AF:

0.000248

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000204

AC:

295

AN:

1447814

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

130

AN XY:

720476

show subpopulations

African (AFR)

AF:

0.000181

AC:

AN:

33082

American (AMR)

AF:

0.000225

AC:

AN:

44356

Ashkenazi Jewish (ASJ)

AF:

0.0000777

AC:

AN:

25730

East Asian (EAS)

AF:

0.000333

AC:

AN:

39036

South Asian (SAS)

AF:

0.000140

AC:

AN:

85836

European-Finnish (FIN)

AF:

0.000287

AC:

AN:

52248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.000201

AC:

222

AN:

1102222

Other (OTH)

AF:

0.000252

AC:

AN:

59602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

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:

0.000140

AC:

AN:

150326

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

73306

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

40944

American (AMR)

AF:

0.000133

AC:

AN:

15048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3446

East Asian (EAS)

AF:

0.000194

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4750

European-Finnish (FIN)

AF:

0.000195

AC:

AN:

10238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000163

AC:

AN:

67468

Other (OTH)

AF:

0.00

AC:

AN:

2052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

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:

0.000271

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nijmegen breakage syndrome-like disorder

Pathogenic:7

Oct 13, 2021

Sema4, Sema4

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

Oct 03, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS3, PM2

Apr 20, 2016

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 22, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 04, 2024

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Pathogenic:3

Jan 13, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2165dupA pathogenic mutation, located in coding exon 13 of the RAD50 gene, results from a duplication of A at nucleotide position 2165, causing a translational frameshift with a predicted alternate stop codon (p.E723Gfs*5). This alteration has been reported multiple individuals diagnosed with breast or prostate cancer (Lin PH et al. Oncotarget. 2016 Feb;7:8310-20; Fan C et al. Int J Cancer, 2018 10;143:1935-1942; Goidescu IG et al. Clujul Med, 2018 Apr;91:157-165; Wang YA et al. BMC Cancer, 2018 03;18:315; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration was also identified in trans with c.3109_3111del in an individual with bone marrow failure, microcephaly, skin pigmentation, nail dysplasia, dental loss and dysmorphia (Chansel-Da Cruz M et al. Cell Rep, 2020 12;33:108559). Of note, this alteration is also known as c.2157dupA in published literature. 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.

May 05, 2025

Unidad de Genética Molecular HGU Elche, Hospital General Universitario de Elche

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1 very strong; PP5 moderate; PM2 supporting

Feb 02, 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.Glu723Glyfs*5) in the RAD50 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD50 are known to be pathogenic (PMID: 19409520). 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 cancer (PMID: 25452441, 26824983). This variant is also known as c.2157dupA. ClinVar contains an entry for this variant (Variation ID: 141045). For these reasons, this variant has been classified as Pathogenic.

not provided

Pathogenic:2Uncertain:1

Jan 03, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); Frameshift variant predicted to result in protein truncation and nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Observed in individuals with breast and/or ovarian cancer (Couch et al., 2015; Lin et al., 2016; Lilyquist et al., 2017; Goidescu et al., 2018); This variant is associated with the following publications: (PMID: 32832836, 26824983, 30755392, 31159747, 26689913, 33378670, 35768433, 34803902, 34680501, 29739316, 35595529, 29566657, 31742824, 33804961, 29726012, 32295079, 25452441, 16385572, 29785153, 28888541)

Jan 01, 2020

GeneKor MSA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is a duplication of 1 nucleotide in exon 13 of RAD50 mRNA (c.2165dupA). causing a frameshift at codon 723. This creates a premature translational stop signal (p.Glu723Glyfs*5) and is expected to result in an absent or disrupted protein product. Truncating mutations in RAD50 are known to be pathogenic. The mutation database ClinVar contains an entry for this variant (Variation ID: 37377/).

Nov 19, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population, 0.00042 (8/19162 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast or ovarian cancer (PMIDs: 31742824 (2020), 26824983 (2016), and 25452441 (2015)). Based on the available information, this variant is classified as pathogenic.

Breast and/or ovarian cancer

Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:case-control

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.13

Mutation Taster

=0/200

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over