rs28903085

chr5-132575843-A-Cchr5-132575843-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005732.4(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 NM_005732.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0120

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.

• 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 GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD50	NM_005732.4	c.280A>C	p.Ile94Leu	missense_variant	3/25	ENST00000378823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8	c.280A>C	p.Ile94Leu	missense_variant	3/25	1	NM_005732.4	P1

Frequencies

GnomAD3 genomes AF: 0.00319 AC: 485 AN: 152234 Hom.: 2 Cov.: 32

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.: 5 AF XY: 0.00348 AC XY: 473 AN XY: 135844

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.: 25 Cov.: 31 AF XY: 0.00456 AC XY: 3294 AN XY: 722270

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.: 2 Cov.: 32 AF XY: 0.00307 AC XY: 229 AN XY: 74518

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.: 5

Bravo AF: 0.00328

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00347 AC: 421

Asia WGS AF: 0.00260 AC: 9 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

Submissions by phenotype

Nijmegen breakage syndrome-like disorder Benign:4

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	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 16, 2020	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RAD50: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 03, 2023	- -
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) -

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	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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	T
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	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.70	N;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.30	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	T
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

Other links and lift over

dbSNP: rs28903085; hg19: chr5-131911535; COSMIC: COSV54756699; COSMIC: COSV54756699;