NM_005732.4:c.572C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_005732.4(RAD50):c.572C>T(p.Thr191Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,612,294 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T191A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0043 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 3 hom. )

Consequence

RAD50
NM_005732.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 7.50

Publications

18 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: Benign. The variant received -16 ACMG points.

BP6

Variant 5-132579882-C-T is Benign according to our data. Variant chr5-132579882-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 37382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132579882-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 37382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132579882-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 37382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132579882-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 37382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132579882-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 37382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132579882-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 37382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132579882-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 37382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132579882-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 37382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132579882-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 37382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132579882-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 37382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00433 (659/152218) while in subpopulation AFR AF = 0.0144 (600/41536). AF 95% confidence interval is 0.0135. There are 6 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD50	NM_005732.4 link	c.572C>T	p.Thr191Ile	missense_variant	Exon 5 of 25	ENST00000378823.8	NP_005723.2	Q92878-1A5D6Y3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8 link	c.572C>T	p.Thr191Ile	missense_variant	Exon 5 of 25	1	NM_005732.4	ENSP00000368100.4		Q92878-1
ENSG00000283782	ENST00000638452.2 link	c.275C>T	p.Thr92Ile	missense_variant	Exon 7 of 27	5		ENSP00000492349.2		A0A1W2PQ90

Frequencies

GnomAD3 genomes

AF:

0.00432

AC:

657

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0144

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00145

AC:

363

AN:

250440

AF XY:

0.00117

show subpopulations

Gnomad AFR exome

AF:

0.0144

Gnomad AMR exome

AF:

0.000753

Gnomad ASJ exome

AF:

0.00696

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.000665

AC:

971

AN:

1460076

Hom.:

Cov.:

AF XY:

0.000585

AC XY:

425

AN XY:

726454

show subpopulations

African (AFR)

AF:

0.0158

AC:

528

AN:

33410

American (AMR)

AF:

0.000850

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00674

AC:

176

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000104

AC:

116

AN:

1110572

Other (OTH)

AF:

0.00139

AC:

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00433

AC:

659

AN:

152218

Hom.:

Cov.:

AF XY:

0.00433

AC XY:

322

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0144

AC:

600

AN:

41536

American (AMR)

AF:

0.00137

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67994

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00181

Hom.:

Bravo

AF:

0.00487

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00177

AC:

215

Asia WGS

AF:

0.000578

AC:

AN:

3472

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 08, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dec 11, 2014

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jan 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 29, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The RAD50 c.572C>T (p.Thr191Ile) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant; however they are not definitive and the predictions have yet to be confirmed by published functional studies. This variant was found in 210/119642 control chromosomes (1 homozygote), predominantly observed in the African subpopulation at a frequency of 0.0147207 (146/9918). This frequency is about 236 times the estimated maximal expected allele frequency of a pathogenic RAD50 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. A large case-control study that used 2,984 breast cancer cases and 7,545 controls did not find an elevated risk for breast cancer due to this variant; instead, a protective effect was observed (OR: 0.44; p=0.0069) (Haiman_2013). In addition, multiple clinical diagnostic laboratories have classified this variant as benign/likely benign. Taken together, this variant is classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary cancer-predisposing syndrome

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 25, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Nijmegen breakage syndrome-like disorder

Benign:2

Aug 09, 2016

Counsyl

Significance:Benign

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. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.039

.;.;.;T;T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;.;D;D;D;D

MetaRNN

Benign

0.0083

T;T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

2.0

.;.;.;.;M;.

PhyloP100

7.5

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.7

.;.;.;N;.;N

REVEL

Benign

0.12

Sift

Benign

0.049

.;.;.;D;.;D

Sift4G

Benign

0.10

.;.;.;T;T;T

Polyphen

0.58

.;.;.;.;P;.

Vest4

0.52

MVP

0.53

ClinPred

0.029

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.50

gMVP

0.35

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 11

DS_AL_spliceai

0.22

Position offset: -20

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