rs772250365

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_005732.4(RAD50):c.454A>T(p.Asn152Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,461,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N152S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

RAD50
NM_005732.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.31

Publications

1 publications found

Variant links:

COSMIC-nc: COSV105839167

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: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD50	NM_005732.4 link	c.454A>T	p.Asn152Tyr	missense_variant	Exon 4 of 25	ENST00000378823.8	NP_005723.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8 link	c.454A>T	p.Asn152Tyr	missense_variant	Exon 4 of 25	1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000638452.2 link	c.157A>T	p.Asn53Tyr	missense_variant	Exon 6 of 27	5		ENSP00000492349.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251392

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1111746

Other (OTH)

AF:

0.0000166

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Jul 28, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.N152Y variant (also known as c.454A>T), located in coding exon 4 of the RAD50 gene, results from an A to T substitution at nucleotide position 454. The asparagine at codon 152 is replaced by tyrosine, an amino acid with dissimilar properties. This alteration was identified in 1/1824 patients diagnosed with triple negative breast cancer and unselected for family history; this cohort underwent panel testing for 17 cancer predisposition genes (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 152 of the RAD50 protein (p.Asn152Tyr). This variant is present in population databases (rs772250365, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 184750). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAD50 protein function with a positive 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. -

not specified

Uncertain:1

May 19, 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.454A>T (p.Asn152Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 2.4e-05 in 251392 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.454A>T has been observed in individual(s) affected with Breast cancer (Couch_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome-Like Disorder. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 184750). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Nijmegen breakage syndrome-like disorder

Uncertain:1

Aug 14, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RAD50 c.454A>T (p.Asn152Tyr) missense change has a maximum subpopulation frequency of 0.0044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, but this prediction has not been confirmed by functional studies. This variant has been reported in 1 out of 1824 individuals diagnosed with triple-negative breast cancer and unselected for family history (PMID: 25452441). It has been also reported in 5 out of 3579 African males diagnosed with prostate cancer (PMID: 32832836). This variant has not been reported in individuals with RAD50-associated conditions. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

.;.;.;T;T;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

.;.;D;D;D;D

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.8

.;.;.;.;M;.

PhyloP100

7.3

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-4.1

.;.;.;D;.;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0020

.;.;.;D;.;D

Sift4G

Uncertain

0.031

.;.;.;D;D;D

Polyphen

1.0

.;.;.;.;D;.

Vest4

0.92

MutPred

0.55

.;.;.;.;Loss of solvent accessibility (P = 0.1362);Loss of solvent accessibility (P = 0.1362);

MVP

0.69

ClinPred

0.91

GERP RS

5.7

Varity_R

0.70

gMVP

0.62

Mutation Taster

=80/20

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over