rs28903085

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_005732.4(RAD50):c.280A>C(p.Ile94Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,602,792 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I94M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0032 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 25 hom. )

Consequence

RAD50
NM_005732.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.0120

Publications

28 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056197047).

BP6

Variant 5-132575843-A-C is Benign according to our data. Variant chr5-132575843-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD50	NM_005732.4 link	c.280A>C	p.Ile94Leu	missense_variant	Exon 3 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.280A>C	p.Ile94Leu	missense_variant	Exon 3 of 25	1	NM_005732.4	ENSP00000368100.4		Q92878-1
ENSG00000283782	ENST00000638452.2 link	c.-18A>C		5_prime_UTR_variant	Exon 5 of 27	5		ENSP00000492349.2		A0A1W2PQ90

Frequencies

GnomAD3 genomes

AF:

0.00319

AC:

485

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00497

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00343

AC:

863

AN:

251344

AF XY:

0.00348

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.00526

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.00415

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00457

AC:

6633

AN:

1450440

Hom.:

Cov.:

AF XY:

0.00456

AC XY:

3294

AN XY:

722270

show subpopulations

African (AFR)

AF:

0.000843

AC:

AN:

33220

American (AMR)

AF:

0.00268

AC:

120

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00514

AC:

134

AN:

26070

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39618

South Asian (SAS)

AF:

0.00555

AC:

477

AN:

86020

European-Finnish (FIN)

AF:

0.00103

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00644

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00501

AC:

5516

AN:

1101640

Other (OTH)

AF:

0.00438

AC:

263

AN:

60002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

333

666

998

1331

1664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

224

448

672

896

1120

<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:

0.00318

AC:

484

AN:

152352

Hom.:

Cov.:

AF XY:

0.00307

AC XY:

229

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41586

American (AMR)

AF:

0.00294

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00497

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00497

AC:

338

AN:

68032

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

101

126

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:

0.00425

Hom.:

Bravo

AF:

0.00328

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00347

AC:

421

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00485

EpiControl

AF:

0.00557

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nijmegen breakage syndrome-like disorder

Benign:5

Sep 30, 2016

Counsyl

Significance:Likely 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. -

Apr 25, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 15, 2016

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 16, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 06, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24093751, 20981092, 14684699, 27884173, 27153395, 23555315, 26483394, 16385572, 27782108, 28492532, 28202063, 26209080) -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RAD50: BP4, BS2 -

Jul 03, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Dec 11, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 31, 2020

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RAD50 c.280A>C (p.Ile94Leu) results in a conservative amino acid change located in the Rad50/SbcC-type AAA domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 255166 control chromosomes, predominantly at a frequency of 0.0061 within the South Asian subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 98-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Further evidence in support of a benign polymorphism is provided by a recent study in Arabic individuals (a population underrepresented in publicly available databases) reporting the variant as benign based on a population frequency of >1% and its presence in the homozygous state in multiple individuals who lack the reported phenotype (Abouelhoda_2016). c.280A>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Heikkinen_2003, Tommiska_2006, Young_2018) but was also reported in controls (e.g. Heikkinen_2003, Kurki_2014). In addition, one family with breast cancer history was documented with one unaffected and two affected sisters carrying the variant (Jalkh_2017). These data do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Hereditary cancer-predisposing syndrome

Benign:2

Nov 20, 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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.069

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

2.4

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.063

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.0037

MetaRNN

Benign

0.0056

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.70

N;.

PhyloP100

-0.012

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

.;N

REVEL

Benign

0.071

Sift

Benign

0.35

.;T

Sift4G

Benign

0.23

T;T

Polyphen

0.0

B;.

Vest4

0.17

MutPred

0.48

Loss of catalytic residue at I94 (P = 0.0063);Loss of catalytic residue at I94 (P = 0.0063);

MVP

0.23

ClinPred

0.0039

GERP RS

-10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.070

gMVP

0.46

Mutation Taster

=299/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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