chr5-132575843-A-C

Position:

chr5-132575843-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000378823.8(RAD50):c.280A>C(p.Ile94Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,602,792 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I94M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0032 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 25 hom. )

Consequence

RAD50
ENST00000378823.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.0120

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056197047).

BP6

Variant 5-132575843-A-C is Benign according to our data. Variant chr5-132575843-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 128012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132575843-A-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD50	NM_005732.4 linkuse as main transcript	c.280A>C	p.Ile94Leu	missense_variant	3/25	ENST00000378823.8	NP_005723.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8 linkuse as main transcript	c.280A>C	p.Ile94Leu	missense_variant	3/25	1	NM_005732.4	ENSP00000368100	P1	Q92878-1

Frequencies

GnomAD3 genomes

AF:

0.00319

AC:

485

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00497

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00343

AC:

863

AN:

251344

Hom.:

AF XY:

0.00348

AC XY:

473

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.00526

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00608

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.00415

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00457

AC:

6633

AN:

1450440

Hom.:

Cov.:

AF XY:

0.00456

AC XY:

3294

AN XY:

722270

show subpopulations

Gnomad4 AFR exome

AF:

0.000843

Gnomad4 AMR exome

AF:

0.00268

Gnomad4 ASJ exome

AF:

0.00514

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00555

Gnomad4 FIN exome

AF:

0.00103

Gnomad4 NFE exome

AF:

0.00501

Gnomad4 OTH exome

AF:

0.00438

GnomAD4 genome

AF:

0.00318

AC:

484

AN:

152352

Hom.:

Cov.:

AF XY:

0.00307

AC XY:

229

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00497

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00497

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00443

Hom.:

Bravo

AF:

0.00328

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00347

AC:

421

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00485

EpiControl

AF:

0.00557

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nijmegen breakage syndrome-like disorder

Benign:4

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 30, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 25, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 15, 2016	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2020	This variant is associated with the following publications: (PMID: 24093751, 20981092, 14684699, 27884173, 27153395, 23555315, 26483394, 16385572, 27782108, 28492532, 28202063, 26209080) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RAD50: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 03, 2023	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2020	Variant summary: RAD50 c.280A>C (p.Ile94Leu) results in a conservative amino acid change located in the Rad50/SbcC-type AAA domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 255166 control chromosomes, predominantly at a frequency of 0.0061 within the South Asian subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 98-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 South Asian origin. Further evidence in support of a benign polymorphism is provided by a recent study in Arabic individuals (a population underrepresented in publicly available databases) reporting the variant as benign based on a population frequency of >1% and its presence in the homozygous state in multiple individuals who lack the reported phenotype (Abouelhoda_2016). c.280A>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Heikkinen_2003, Tommiska_2006, Young_2018) but was also reported in controls (e.g. Heikkinen_2003, Kurki_2014). In addition, one family with breast cancer history was documented with one unaffected and two affected sisters carrying the variant (Jalkh_2017). These data 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. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 11, 2015	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 20, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

2.4

DANN

Benign

0.85

DEOGEN2

Benign

0.063

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.0037

MetaRNN

Benign

0.0056

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.70

N;.

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

.;N

REVEL

Benign

0.071

Sift

Benign

0.35

.;T

Sift4G

Benign

0.23

T;T

Polyphen

0.0

B;.

Vest4

0.17

MutPred

0.48

Loss of catalytic residue at I94 (P = 0.0063);Loss of catalytic residue at I94 (P = 0.0063);

MVP

0.23

ClinPred

0.0039

GERP RS

-10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.070

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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