5-132588729-G-A

Position:

chr5-132588729-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_005732.4(RAD50):c.1094G>A(p.Arg365Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000332 in 1,613,590 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. R365G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

RAD50
NM_005732.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:4O:1

Conservation

PhyloP100: 1.06

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018426448).

BP6

Variant 5-132588729-G-A is Benign according to our data. Variant chr5-132588729-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127990.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=2, Uncertain_significance=8, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD50	NM_005732.4 linkuse as main transcript	c.1094G>A	p.Arg365Gln	missense_variant	8/25	ENST00000378823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8 linkuse as main transcript	c.1094G>A	p.Arg365Gln	missense_variant	8/25	1	NM_005732.4	P1	Q92878-1

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

151772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.000625

Gnomad FIN

AF:

0.000381

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000458

AC:

115

AN:

251162

Hom.:

AF XY:

0.000464

AC XY:

AN XY:

135728

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000652

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000652

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000337

AC:

492

AN:

1461700

Hom.:

Cov.:

AF XY:

0.000351

AC XY:

255

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000504

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000353

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000283

AC:

AN:

151890

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74210

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.000625

Gnomad4 FIN

AF:

0.000381

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000453

Hom.:

Bravo

AF:

0.000234

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000404

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast and ovarian cancer (Lu 2015, Fanale 2020); This variant is associated with the following publications: (PMID: 31159747, 32854451, 30441849, 26689913) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 27, 2022	The frequency of this variant in the general population, 0.0011 (38/33046 chromosomes in the 'Other non-Finnish European' subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals or families with breast/ovarian cancer (PMIDs: 32854451 (2020), 31159747 (2019), 30306255 (2018), 28550065 (2017), 24894818 (2014)), ovarian cancer alone (PMIDs: 30441849 (2018), 26689913 (2015)), and colorectal cancer (PMID: 33563768 (2022)). 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. -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The RAD50 p.Arg365Gln variant was identified in 5 of 10694 proband chromosomes (frequency: 0.000468) from individuals or families with breast and ovarian cancer and was not identified in 1121 control chromosomes from healthy individuals (Damiola_2014_24894818; Lu_2015_PMID: 26689913). The variant was also identified in dbSNP (ID: rs146370443), ClinVar (conflicting interpretations of pathogenicity: one likely benign submission by Ambry Genetics and four VUS submissions by GeneDx, Invitae, Fulgent Genetics and GeneKor MSA; associated conditions are Nijmegen breakage syndrome-like disorder and Hereditary cancer-predisposing syndrome. The variant was identified in control databases in 122 of 282506 chromosomes at a frequency of 0.000432 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was not identified in the Cosmic and LOVD 3.0 databases. The variant was observed in the following populations: European (non-Finnish) in 79 of 128920 chromosomes (freq: 0.000613), East Asian in 12 of 19952 chromosomes (freq: 0.000601), South Asian in 16 of 30592 chromosomes (freq: 0.000523), Other in 3 of 7210 chromosomes (freq: 0.000416), Latino in 8 of 35398 chromosomes (freq: 0.000226), European (Finnish) in 4 of 25110 chromosomes (freq: 0.000159), while the variant was not observed in the African, and Ashkenazi Jewish populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg365 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 01, 2019	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 365 of the RAD50 protein (p.Arg365Gln). This variant is present in population databases (rs146370443, gnomAD 0.06%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 24894818, 26689913, 30306255, 30441849). ClinVar contains an entry for this variant (Variation ID: 127990). 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 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. -

RAD50-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2024

The RAD50 c.1094G>A variant is predicted to result in the amino acid substitution p.Arg365Gln. This variant has been reported as a variant of uncertain significance in patients tested using a panel of genes for hereditary cancer syndrome (Table S5, Tsaousis et al. 2019. PubMed ID 3115974), as well as in patients with breast or ovarian cancer (Table S9, Bonache et al. 2018. PubMed ID: 30306255; Damiola et al. 2014. PubMed ID 24894818; Table S1, Koczkowska et al. 2018. PubMed ID: 30441849; Table S12, Lu et al. 2015. PubMed ID 26689913; Table 4, Fanale et al. 2020. PubMed ID 32854451). It has also been reported in a metastatic liver biopsy specimen (Table S2, Parachoniak et al. 2017. PubMed ID: 28550065). This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127990/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 06, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 365 of the RAD50 protein (p.Arg365Gln). This variant is present in population databases (rs146370443, gnomAD 0.06%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 24894818, 26689913, 30306255, 30441849). ClinVar contains an entry for this variant (Variation ID: 127990). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

Nijmegen breakage syndrome-like disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 27, 2023

Variant summary: RAD50 c.1094G>A (p.Arg365Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 251162 control chromosomes. The observed variant frequency is approximately 7.33 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 benign. c.1094G>A has been reported in the literature in individuals affected with Breast And Ovarian Cancer Syndrome as well as other types of cancer (example, Lu_2015, Bonache_2018, Damiola_2014, Koczkowska_2018, Parachoniak_2017, Tsaousis_2019, Young_2016). These reports 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, six classified the variant as a VUS while one classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Familial cancer of breast;C2751318:Nijmegen breakage syndrome-like disorder

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 06-11-2020 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.079

.;.;.;T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.77

.;.;T;T;T

M_CAP

Benign

0.0070

MetaRNN

Benign

0.018

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.0

.;.;.;M;.

MutationTaster

Benign

0.95

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.53

.;.;.;.;N

REVEL

Benign

0.077

Sift

Benign

0.35

.;.;.;.;T

Sift4G

Benign

0.45

.;.;.;T;T

Polyphen

0.013

.;.;.;B;.

Vest4

0.21

MVP

0.41

ClinPred

0.030

GERP RS

4.2

Varity_R

0.026

gMVP

0.13

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

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