rs28903092

chr5-132595780-G-Achr5-132595780-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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R726C) has been classified as Uncertain significance.

• 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:7 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]

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: {Uncertain_significance=6, Likely_benign=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD50	NM_005732.4	c.2177G>A	p.Arg726His	missense_variant	13/25	ENST00000378823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8	c.2177G>A	p.Arg726His	missense_variant	13/25	1	NM_005732.4	P1

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:7 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	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). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 24, 2020	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	GeneKor MSA	Aug 01, 2018	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 05, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 19, 2021	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

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -

RAD50-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 22, 2022

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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2022

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) -

Premature ovarian insufficiency Uncertain:1

Uncertain significance, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Jan 11, 2018

- -

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
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.049	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	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;