rs28903092

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005732.4(RAD50):c.2177G>A(p.Arg726His) variant causes a missense change. The variant allele was found at a frequency of 0.000133 in 1,611,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R726L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

RAD50
NM_005732.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1O:1

Conservation

PhyloP100: 5.00

Publications

15 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_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.049025178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD50	NM_005732.4 link	c.2177G>A	p.Arg726His	missense_variant	Exon 13 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.2177G>A	p.Arg726His	missense_variant	Exon 13 of 25	1	NM_005732.4	ENSP00000368100.4		Q92878-1
ENSG00000283782	ENST00000638452.2 link	c.1880G>A	p.Arg627His	missense_variant	Exon 15 of 27	5		ENSP00000492349.2		A0A1W2PQ90

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000145

AC:

AN:

248808

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.000371

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00110

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000125

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000122

AC:

178

AN:

1459572

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

726176

show subpopulations

African (AFR)

AF:

0.000628

AC:

AN:

33452

American (AMR)

AF:

0.000201

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00146

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52288

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000792

AC:

AN:

1110986

Other (OTH)

AF:

0.000265

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

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:

0.000236

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41554

American (AMR)

AF:

0.000392

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000250

Hom.:

Bravo

AF:

0.000310

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 726 of the RAD50 protein (p.Arg726His). This variant is present in population databases (rs28903092, gnomAD 0.1%). This missense change has been observed in individual(s) with breast cancer (PMID: 16385572, 25503501, 32658311). ClinVar contains an entry for this variant (Variation ID: 128001). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAD50 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 24, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Aug 01, 2018

GeneKor MSA

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:2

Apr 07, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RAD50 c.2177G>A (p.Arg726His) results in a non-conservative amino acid change located in the RAD50, zinc hook domain (IPR013134) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 248808 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RAD50 causing Nijmegen Breakage Syndrome-Like Disorder (0.00014 vs 0.0024), allowing no conclusion about variant significance. To our knowledge, c.2177G>A has not been reported in the literature in individuals affected with Nijmegen Breakage Syndrome-Like Disorder, and 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: 32658311, 33471991, 31980526, 25503501, 16385572, 31159747, 30924587, 34572942, 22905743, 32868316, 29555771, 32699558, 39315505, 35534704, 31874108, 39256447). ClinVar contains an entry for this variant (Variation ID: 128001). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Aug 19, 2021

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the RAD50 gene demonstrated a sequence change, c.2177G>A, in exon 13 that results in an amino acid change, p.Arg726His. This sequence change has been described in the gnomAD database with frequency of 0.11% in the Ashkenazi Jewish subpopulation (dbSNP rs28903092). The p.Arg726His change affects a moderately conserved amino acid residue located in a domain of the RAD50 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg726His substitution. This sequence change has been reported in individuals who had germline genetic testing based on a personal or family history of breast cancer (PMID: 31159747, 16385572, 25503501). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg726His change remains unknown at this time. -

not provided

Uncertain:2

Nov 05, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RAD50 c.2177G>A (p.Arg726His) variant has been reported in the published literature in individuals with breast cancer (PMID: 32658311 (2021), 25503501 (2015), 16385572 (2006)) and in an individual undergoing hereditary cancer testing (PMID: 31159747 (2019)). In a large scale breast cancer association study, this variant has been observed in breast cancer cases, as well as reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.0011 (11/10322 chromosomes in Ashkenazi Jewish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jul 15, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); Identified in individuals with personal or family history of breast or other cancer and in an individual with primary ovarian insufficiency (Tommiska et al., 2006; Maxwell et al., 2015; Perkins et al., 2018; Tucker et al., 2019); This variant is associated with the following publications: (PMID: 29555771, 31159747, 30924587, 31980526, 16385572, 25503501) -

Nijmegen breakage syndrome-like disorder

Uncertain:1Other:1

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Uncertain significance and reported on 08-31-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RAD50-related disorder

Uncertain:1

Dec 22, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RAD50 c.2177G>A variant is predicted to result in the amino acid substitution p.Arg726His. This variant has been reported in individuals with breast cancer, although its pathogenicity was not established (Tommiska et al. 2006. PubMed ID: 16385572; Maxwell et al. 2015. PubMed ID: 25503501, supplementary table 1). It was also reported as a variant of uncertain significance in individuals with a possible hereditary cancer predisposition syndrome (Perkins et al. 2018. PubMed ID: 29555771, Table S2; Tsaousis et al. 2019. PubMed ID: 31159747, Table S5) and in one individual with premature ovarian insufficiency (Tucker et al. 2019. PubMed ID: 30924587). This variant is reported in 0.11% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-131931472-G-A). In ClinVar, it has conflicting interpretations, including uncertain significance and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/128001/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Premature ovarian insufficiency

Uncertain:1

Jan 11, 2018

Reproductive Development, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.068

.;.;.;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;.;D;D

M_CAP

Benign

0.0045

MetaRNN

Benign

0.049

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

.;.;.;M

PhyloP100

5.0

PrimateAI

Uncertain

0.56

REVEL

Benign

0.13

Sift4G

Benign

0.54

.;.;.;T

Polyphen

0.86

.;.;.;P

Vest4

0.63

MVP

0.55

ClinPred

0.061

GERP RS

6.1

Varity_R

0.47

gMVP

0.41

Mutation Taster

=54/46

polymorphism

(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