rs144253015

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_005732.4(RAD50):c.3455G>A(p.Arg1152Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000577 in 1,611,972 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. R1152L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

RAD50
NM_005732.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 9.59

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 links:

TH2LCRR (HGNC:40495): (T helper type 2 locus control region associated RNA)

TH2LCRR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_005732.4

BP4

Computational evidence support a benign effect (MetaRNN=0.062730014).

BP6

Variant 5-132637180-G-A is Benign according to our data. Variant chr5-132637180-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128019.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD50	NM_005732.4 linkuse as main transcript	c.3455G>A	p.Arg1152Gln	missense_variant	22/25	ENST00000378823.8
TH2LCRR	NR_132124.1 linkuse as main transcript	n.153+978C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8 linkuse as main transcript	c.3455G>A	p.Arg1152Gln	missense_variant	22/25	1	NM_005732.4	P1	Q92878-1

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000821

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000954

AC:

AN:

251442

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1459830

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726248

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.000223

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.000819

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000757

Hom.:

Bravo

AF:

0.000348

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2014	RAD50 has only been recently described in association with cancer predisposition and the risks are not well understood.This variant is denoted RAD50 c.3455G>A at the cDNA level, p.Arg1152Gln (R1152Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Arg1152Gln was observed with an allele frequency of 0.2% (11/4406) in African Americans in the NHLBI Exome Sequencing Project, which is not frequent enough to be considered a common benign variant. This variant is a semi-conservative substitution in which a positive polar amino acid is replaced with a neutral polar one, altering a position that is fully conserved throughout evolution and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function but lean toward benign. The currently available evidence about this variant does not allow us to predict whether RAD50 Arg1152Gln is a pathogenic variant or a benign variant, and it is therefore classified as having unknown significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 30, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 18, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -

RAD50-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 29, 2022

The RAD50 c.3455G>A variant is predicted to result in the amino acid substitution p.Arg1152Gln. This variant was reported in an individual with breast or Lynch syndrome (Table S1 - Velázquez et al. 2020. PubMed ID: 32522261). This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-131972872-G-A). In ClinVar this variant has conflicting interpretations of pathogenicity of benign, likely benign, and uncertain (https://ncbi.nlm.nih.gov/clinvar/variation/128019/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Nijmegen breakage syndrome-like disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Aug 23, 2021

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.044

BayesDel_noAF

Uncertain

0.12

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Benign

0.050

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

1.0

M_CAP

Benign

0.031

MetaRNN

Benign

0.063

T;T;T;T

MetaSVM

Benign

-0.77

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.66

Polyphen

0.11

.;.;.;B

Vest4

0.82

MVP

0.60

ClinPred

0.16

GERP RS

5.9

Varity_R

0.24

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over