rs2230017

chr5-132579882-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005732.4(RAD50):c.572C>T(p.Thr191Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,612,294 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T191T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0043 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (3 hom.)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.50

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 5-132579882-C-T is Benign according to our data. Variant chr5-132579882-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 37382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00433 (659/152218) while in subpopulation AFR AF= 0.0144 (600/41536). AF 95% confidence interval is 0.0135. There are 6 homozygotes in gnomad4. There are 322 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD50	NM_005732.4	c.572C>T	p.Thr191Ile	missense_variant	5/25	ENST00000378823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8	c.572C>T	p.Thr191Ile	missense_variant	5/25	1	NM_005732.4	P1

Frequencies

GnomAD3 genomes AF: 0.00432 AC: 657 AN: 152100 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00145 AC: 363 AN: 250440 Hom.: 3 AF XY: 0.00117 AC XY: 159 AN XY: 135432

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.00696

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.000665 AC: 971 AN: 1460076 Hom.: 3 Cov.: 31 AF XY: 0.000585 AC XY: 425 AN XY: 726454

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00674

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00433 AC: 659 AN: 152218 Hom.: 6 Cov.: 32 AF XY: 0.00433 AC XY: 322 AN XY: 74416

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00136 Hom.: 1

Bravo AF: 0.00487

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00177 AC: 215

Asia WGS AF: 0.000578 AC: 2 AN: 3472

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 11, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 29, 2016	Variant summary: The RAD50 c.572C>T (p.Thr191Ile) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant; however they are not definitive and the predictions have yet to be confirmed by published functional studies. This variant was found in 210/119642 control chromosomes (1 homozygote), predominantly observed in the African subpopulation at a frequency of 0.0147207 (146/9918). This frequency is about 236 times the estimated maximal expected allele frequency of a pathogenic RAD50 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. A large case-control study that used 2,984 breast cancer cases and 7,545 controls did not find an elevated risk for breast cancer due to this variant; instead, a protective effect was observed (OR: 0.44; p=0.0069) (Haiman_2013). In addition, multiple clinical diagnostic laboratories have classified this variant as benign/likely benign. Taken together, this variant is classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 25, 2014	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. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Nijmegen breakage syndrome-like disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Counsyl

Aug 09, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0083	T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
Polyphen		0.58	.;.;.;.;P;.
Vest4		0.52
MVP		0.53
ClinPred		0.029	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.50
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 11
DS_AL_spliceai		0.22		Position offset: -20

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

Publications

LitVar

Other links and lift over

dbSNP: rs2230017; hg19: chr5-131915574; COSMIC: COSV99037118;