chr5-132579882-C-T

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

1
5
12

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

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
RAD50NM_005732.4 linkc.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
RAD50ENST00000378823.8 linkc.572C>T p.Thr191Ile missense_variant Exon 5 of 25 1 NM_005732.4 ENSP00000368100.4 Q92878-1
ENSG00000283782ENST00000638452.2 linkc.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.:
6
Cov.:
32
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.:
3
Cov.:
31
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:
38
AN:
44700
Ashkenazi Jewish (ASJ)
AF:
0.00674
AC:
176
AN:
26112
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39618
South Asian (SAS)
AF:
0.0000348
AC:
3
AN:
86194
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53402
Middle Eastern (MID)
AF:
0.00451
AC:
26
AN:
5760
European-Non Finnish (NFE)
AF:
0.000104
AC:
116
AN:
1110572
Other (OTH)
AF:
0.00139
AC:
84
AN:
60308
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.456
Heterozygous variant carriers
0
51
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
0
22
44
66
88
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.:
6
Cov.:
32
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:
21
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.00778
AC:
27
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10588
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000103
AC:
7
AN:
67994
Other (OTH)
AF:
0.00189
AC:
4
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
Heterozygous variant carriers
0
30
60
91
121
151
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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.:
1
Bravo
AF:
0.00487
ESP6500AA
AF:
0.0109
AC:
48
ESP6500EA
AF:
0.00128
AC:
11
ExAC
AF:
0.00177
AC:
215
Asia WGS
AF:
0.000578
AC:
2
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
T
BayesDel_noAF
Benign
-0.33
CADD
Uncertain
24
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
D
LIST_S2
Uncertain
0.92
.;.;D;D;D;D
MetaRNN
Benign
0.0083
T;T;T;T;T;T
MetaSVM
Benign
-1.2
T
MutationAssessor
Benign
2.0
.;.;.;.;M;.
PhyloP100
7.5
PrimateAI
Uncertain
0.74
T
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
T
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

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

Other links and lift over

dbSNP: rs2230017; hg19: chr5-131915574; COSMIC: COSV99037118; API