5-132589662-A-G

Position:

chr5-132589662-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_005732.4(RAD50):c.1277A>G(p.Gln426Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,602,748 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).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

RAD50
NM_005732.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:1

Conservation

PhyloP100: 8.86

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:

ENSG00000283782 (HGNC:):

ENSG00000283782 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26830512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD50	NM_005732.4 linkuse as main transcript	c.1277A>G	p.Gln426Arg	missense_variant	9/25	ENST00000378823.8	NP_005723.2	Q92878-1A5D6Y3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8 linkuse as main transcript	c.1277A>G	p.Gln426Arg	missense_variant	9/25	1	NM_005732.4	ENSP00000368100.4		Q92878-1
ENSG00000283782	ENST00000640655.2 linkuse as main transcript	c.980A>G	p.Gln327Arg	missense_variant	10/26	5		ENSP00000491596.2		A0A1W2PQ90

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00110

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:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000139

AC:

AN:

244864

Hom.:

AF XY:

0.000143

AC XY:

AN XY:

132456

show subpopulations

Gnomad AFR exome

AF:

0.0000638

Gnomad AMR exome

AF:

0.0000597

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:

0.000260

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.000170

AC:

247

AN:

1450414

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

125

AN XY:

720954

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.0000691

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:

0.000214

Gnomad4 OTH exome

AF:

0.0000834

GnomAD4 genome

AF:

0.000144

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0000481

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:

0.000265

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000251

Hom.:

Bravo

AF:

0.000151

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000148

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 17, 2023	The frequency of this variant in the general population, 0.00028 (35/126948 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast and/or ovarian cancer (PMIDs: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/), 34371384 (2021), 32854451 (2020), 31921681 (2019), 31512090 (2019), 31159747 (2019), 30441849 (2018)), and in healthy controls (PMIDs: 24894818 (2014) and 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). In one individual affected with medullary thyroid cancer, the individual was also positive for a pathogenic CHEK2 variant (PMID: 30680046 (2019)). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2014	RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.1277A>G at the cDNA level, p.Gln426Arg (Q426R) at the protein level, and results in the change of a Glutamine to an Arginine (CAA>CGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Gln426Arg has not been observed at significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a semi-conservative substitution in which a a neutral polar amino acid is replaced with a positive polar one, altering a position that is well conserved throughout evolution and is not located in a known functional domain. Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear. -
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:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 13, 2022	The p.Q426R variant (also known as c.1277A>G), located in coding exon 9 of the RAD50 gene, results from an A to G substitution at nucleotide position 1277. The glutamine at codon 426 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in multiple studies of individuals with suspected hereditary breast and/or ovarian cancer syndrome, including patients with male breast cancer, ovarian cancer, and bilateral breast cancer (Urhammer N and Bignon YJ. "Abstract# 3037: Contribution of the Rad50, Mre11A, and NBN genes to HBOC." Cancer Res.2009;69; Koczkowska M et al. Cancers (Basel), 2018 Nov;10;442; Oliver J et al. Front Oncol., 2019 Dec;9:1429; Scarpitta R et al. Breast Cancer Res. Treat., 2019 Dec;178:557-564; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Fanale D et al. Cancers (Basel), 2020 Aug;12:E2415). However, in another study, this variant was not observed in 1313 cases diagnosed with breast cancer before the age of 45 but was reported in 1/1123 controls (Damiola F et al. Breast Cancer Res. 2014 Jun;16:R58). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 426 of the RAD50 protein (p.Gln426Arg). This variant is present in population databases (rs145428112, gnomAD 0.03%). This missense change has been observed in individual(s) with a personal and/or family history of breast, ovarian, and/or pancreatic cancer (PMID: 30441849, 31512090, 31921681, 32854451, 34371384). ClinVar contains an entry for this variant (Variation ID: 127993). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

Nijmegen breakage syndrome-like disorder

Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -

RAD50-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2024

The RAD50 c.1277A>G variant is predicted to result in the amino acid substitution p.Gln426Arg. This variant has been reported in an individual undergoing hereditary cancer testing (Tsaousis et al. 2019. PubMed ID: 31159747, Table S5), in an individual with bilateral breast cancer (Fanale et al. 2020. PubMed ID: 32854451), in an individual with hereditary breast and ovarian cancer (Oliver et al. 2019. PubMed ID: 31921681, Table S1), in at least one individual with ovarian cancer (Koczkowska et al. 2018. PubMed ID: 30441849, Table S1), and in an individual with male breast cancer, pancreatic cancer, and bladder cancer (Scarpitta et al. 2019. PubMed ID: 31512090, Table 1). These studies interpreted this variant as uncertain significance. It is reported in 0.028% 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/127993/). 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

May 27, 2024

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 426 of the RAD50 protein (p.Gln426Arg). This variant is present in population databases (rs145428112, gnomAD 0.03%). This missense change has been observed in individual(s) with a personal and/or family history of breast, ovarian, and/or pancreatic cancer (PMID: 30441849, 31512090, 31921681, 32854451, 34371384) . Five clinical diagnostic laboratories have submitted clinicalsignificance assessments for this variant to ClinVar (Variation ID:127993) after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Multiple in silico algorithms predict that this variant may be damaging to protein structure and 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Dec 27, 2021

Variant summary: RAD50 c.1277A>G (p.Gln426Arg) results in a conservative amino acid change in 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 244864 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.00026 in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.1277A>G, has been reported in the literature as a VUS and/or reporting conflicting interpretations of pathogenicity in settings of multigene panel testing among individuals with a personal- or family history of Breast and/or Ovarian Cancer, and other tumor phenotypes (example, Koczkowska_2018, Scarpitta_2019, Oliver_2019, Tsaousis_2019, Bono_2021), however it was also found in controls (Haiman_2013, Damiola_2014). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. In addition, in a patient who was affected with thyroid cancer, a co-occurrence with another pathogenic variant has been reported (CHEK2 c.444+1G>A; Henn_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

.;.;.;T;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

.;.;T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.27

T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.3

.;.;.;M;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.7

.;.;.;.;N

REVEL

Uncertain

0.35

Sift

Uncertain

0.0010

.;.;.;.;D

Sift4G

Benign

0.16

.;.;.;T;T

Polyphen

0.99

.;.;.;D;.

Vest4

0.80

MVP

0.66

ClinPred

0.20

GERP RS

5.5

Varity_R

0.49

gMVP

0.46

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