rs141989813

chr5-132603380-G-Achr5-132603380-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.2288G>A(p.Arg763His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,613,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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. R763C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 3.07

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=0.02120933).
• BP6: Variant 5-132603380-G-A is Benign according to our data. Variant chr5-132603380-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128003.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD50	NM_005732.4	c.2288G>A	p.Arg763His	missense_variant	14/25	ENST00000378823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8	c.2288G>A	p.Arg763His	missense_variant	14/25	1	NM_005732.4	P1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000331 AC: 83 AN: 250948 Hom.: 0 AF XY: 0.000332 AC XY: 45 AN XY: 135602

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000582

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000413 AC: 603 AN: 1461390 Hom.: 0 Cov.: 31 AF XY: 0.000393 AC XY: 286 AN XY: 727016

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000497

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74426

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000397 Hom.: 1

Bravo AF: 0.000215

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2013	RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.2288G>A at the cDNA level, p.Arg763His (R763H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Arg763His was not observed at significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a conservative substitution of one positive polar amino acid for another, altering a position that is well conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on 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	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	RAD50: BP4 -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 21, 2018	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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 19, 2022

Variant summary: RAD50 c.2288G>A (p.Arg763His) results in a non-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 0.00033 in 250948 control chromosomes, predominantly at a frequency of 0.00058 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2288G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence for causality (eg. Bono_2021, Damiola_2014, etc). 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: two as VUS and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Nijmegen breakage syndrome-like disorder Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

May 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.12
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.021	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.34	T
Polyphen		0.0040	.;.;.;B
Vest4		0.21
MVP		0.60
ClinPred		0.11	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.32

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: rs141989813; hg19: chr5-131939072; COSMIC: COSV54755877;