rs28903092

Variant names:

• chr5-132595780-G-A
• rs28903092
• NM_005732.4:c.2177G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-132595780-G-A
• chr5-132595780-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

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).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2 O:1
• Conservation: PhyloP100: 5.00

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]

ENSG00000283782 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.049025178).
• BP6: Variant 5-132595780-G-A is Benign according to our data. Variant chr5-132595780-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128001.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD50	NM_005732.4	c.2177G>A	p.Arg726His	missense_variant	Exon 13 of 25	ENST00000378823.8	NP_005723.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.2177G>A	p.Arg726His	missense_variant	Exon 13 of 25	1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000640655.2	c.1880G>A	p.Arg627His	missense_variant	Exon 14 of 26	5		ENSP00000491596.2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152164 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000145 AC: 36 AN: 248808 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 134578

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 SAS exome AF: 0.0000327

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.: 0 Cov.: 30 AF XY: 0.000120 AC XY: 87 AN XY: 726176

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00146

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000792

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74452

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.000310

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

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. -

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. -

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

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) -

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. -

not specified Uncertain:1 Benign:1

May 05, 2022

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

Significance: Likely benign

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 (gnomAD). The observed variant frequency is approximately 2 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), suggesting that the variant is benign. c.2177G>A has been reported in the literature in individuals affected with Breast Cancer (e.g. Dorling_2021, Tommiska_2006, Maxwell_2015, Tsaousis_2019, Akcay_2021) and Premature Ovarian Insufficiency (Tucker_2019). In this latter case, the patient also carried a second RAD50 variant without signs of Nijmegen Breakage Syndrome and also had a GREM1 variant (VUS) that may contribute to the Premature Ovarian Insufficiency phenotype. 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. Six ClinVar submitters have assessed the variant since 2014: five classified the variant as of uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

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. -

Nijmegen breakage syndrome-like disorder Uncertain:1 Other:1

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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. -

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	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	.;.;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;.;D;D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.049	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;.;.;M
PrimateAI	Uncertain	0.56	T
REVEL	Benign	0.13
Sift4G	Benign	0.54	.;.;.;T
Polyphen		0.86	.;.;.;P
Vest4		0.63
MVP		0.55
ClinPred		0.061	T
GERP RS		6.1
Varity_R		0.47
gMVP		0.41

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

Other links and lift over

dbSNP: rs28903092; hg19: chr5-131931472; COSMIC: COSV54756229; COSMIC: COSV54756229;