Variant chr5-132579996-GT-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_005732.4(RAD50):c.687del(p.Ser229ArgfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,613,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S229S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

RAD50
NM_005732.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.206

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 Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 5-132579996-GT-G is Pathogenic according to our data. Variant chr5-132579996-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD50	NM_005732.4 linkuse as main transcript	c.687del	p.Ser229ArgfsTer6	frameshift_variant	5/25	ENST00000378823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8 linkuse as main transcript	c.687del	p.Ser229ArgfsTer6	frameshift_variant	5/25	1	NM_005732.4	P1	Q92878-1

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000462

AC:

116

AN:

251160

Hom.:

AF XY:

0.000442

AC XY:

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00462

Gnomad NFE exome

AF:

0.0000969

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000153

AC:

224

AN:

1461080

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

726894

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00395

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000401

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00565

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 28, 2023	The c.687delT pathogenic mutation, located in coding exon 5 of the RAD50 gene, results from a deletion of one nucleotide at nucleotide position 687, causing a translational frameshift with a predicted alternate stop codon (p.S229Rfs*6). This alteration was first reported in 2/151 Finnish familial breast/ovarian cancer individuals as well as in 6/1000 cancer free controls (Heikkinen K, J. Med. Genet. 2003 Dec; 40(12):e131). In a case control study of 317 consecutive newly diagnosed Finnish breast cancer patients and 1000 geographically matched healthy controls, eight breast cancer patients and six controls were carriers (95% CI 1.5–12.5, P = 0.008). Haplotype analysis suggests this is a Finnish founder mutation (Heikkinen K, Carcinogenesis 2006 Aug; 27(8):1). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 14, 2023	Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects RAD50 function (PMID: 14684699, 16385572, 16474176). ClinVar contains an entry for this variant (Variation ID: 185010). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer in that population (PMID: 14684699, 16385572, 16474176, 25452441). It is commonly reported in individuals of Finnish ancestry (PMID: 14684699, 16385572, 16474176, 25452441). This variant is present in population databases (rs760146707, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This sequence change creates a premature translational stop signal (p.Ser229Argfs*6) in the RAD50 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD50 are known to be pathogenic (PMID: 19409520). -

Nijmegen breakage syndrome-like disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 15, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 13, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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