5-132595759-TAA-TAAA

Position:

chr5-132595759-TAA-TAAA

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The NM_005732.4(RAD50):c.2165dupA(p.Glu723fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,598,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

RAD50
NM_005732.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:1

Conservation

PhyloP100: -0.126

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:

ENSG00000283782 (HGNC:):

ENSG00000283782 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1

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

PP5

Variant 5-132595759-T-TA is Pathogenic according to our data. Variant chr5-132595759-T-TA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141045.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=11}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD50	NM_005732.4 linkuse as main transcript	c.2165dupA	p.Glu723fs	frameshift_variant	13/25	ENST00000378823.8	NP_005723.2	Q92878-1A5D6Y3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8 linkuse as main transcript	c.2165dupA	p.Glu723fs	frameshift_variant	13/25	1	NM_005732.4	ENSP00000368100.4		Q92878-1
ENSG00000283782	ENST00000640655.2 linkuse as main transcript	c.1868dupA	p.Glu624fs	frameshift_variant	14/26	5		ENSP00000491596.2		A0A1W2PQ90

Frequencies

GnomAD3 genomes

AF:

0.000140

AC:

AN:

150326

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000195

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000163

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000271

AC:

AN:

239710

Hom.:

AF XY:

0.000246

AC XY:

AN XY:

129936

show subpopulations

Gnomad AFR exome

AF:

0.000192

Gnomad AMR exome

AF:

0.000242

Gnomad ASJ exome

AF:

0.000205

Gnomad EAS exome

AF:

0.000454

Gnomad SAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.000455

Gnomad NFE exome

AF:

0.000248

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000204

AC:

295

AN:

1447814

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

130

AN XY:

720476

show subpopulations

Gnomad4 AFR exome

AF:

0.000181

Gnomad4 AMR exome

AF:

0.000225

Gnomad4 ASJ exome

AF:

0.0000777

Gnomad4 EAS exome

AF:

0.000333

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.000287

Gnomad4 NFE exome

AF:

0.000201

Gnomad4 OTH exome

AF:

0.000252

GnomAD4 genome

AF:

0.000140

AC:

AN:

150326

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

73306

show subpopulations

Gnomad4 AFR

AF:

0.000122

Gnomad4 AMR

AF:

0.000133

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000195

Gnomad4 NFE

AF:

0.000163

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nijmegen breakage syndrome-like disorder

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 20, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 03, 2022	PVS1, PS3, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 26, 2024	- -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Oct 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 19, 2021	The frequency of this variant in the general population, 0.00042 (8/19162 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast or ovarian cancer (PMIDs: 31742824 (2020), 26824983 (2016), and 25452441 (2015)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variant is a duplication of 1 nucleotide in exon 13 of RAD50 mRNA (c.2165dupA). causing a frameshift at codon 723. This creates a premature translational stop signal (p.Glu723Glyfs*5) and is expected to result in an absent or disrupted protein product. Truncating mutations in RAD50 are known to be pathogenic. The mutation database ClinVar contains an entry for this variant (Variation ID: 37377/). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2023	Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); Frameshift variant predicted to result in protein truncation and nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Observed in individuals with breast and/or ovarian cancer (Couch et al., 2015; Lin et al., 2016; Lilyquist et al., 2017; Goidescu et al., 2018); This variant is associated with the following publications: (PMID: 32832836, 26824983, 30755392, 31159747, 26689913, 33378670, 35768433, 34803902, 34680501, 29739316, 35595529, 29566657, 31742824, 33804961, 29726012, 32295079, 25452441, 16385572, 29785153, 28888541) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change creates a premature translational stop signal (p.Glu723Glyfs*5) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 25452441, 26824983). This variant is also known as c.2157dupA. ClinVar contains an entry for this variant (Variation ID: 141045). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 13, 2022	The c.2165dupA pathogenic mutation, located in coding exon 13 of the RAD50 gene, results from a duplication of A at nucleotide position 2165, causing a translational frameshift with a predicted alternate stop codon (p.E723Gfs*5). This alteration has been reported multiple individuals diagnosed with breast or prostate cancer (Lin PH et al. Oncotarget. 2016 Feb;7:8310-20; Fan C et al. Int J Cancer, 2018 10;143:1935-1942; Goidescu IG et al. Clujul Med, 2018 Apr;91:157-165; Wang YA et al. BMC Cancer, 2018 03;18:315; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration was also identified in trans with c.3109_3111del in an individual with bone marrow failure, microcephaly, skin pigmentation, nail dysplasia, dental loss and dysmorphia (Chansel-Da Cruz M et al. Cell Rep, 2020 12;33:108559). Of note, this alteration is also known as c.2157dupA in published literature. 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. -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

CZECANCA consortium

Jun 11, 2019

- -

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