NM_005732.4(RAD50):c.3489_3495del (p.Glu1164fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 8, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000226547.9

Allele description [Variation Report for NM_005732.4(RAD50):c.3489_3495del (p.Glu1164fs)]

NM_005732.4(RAD50):c.3489_3495del (p.Glu1164fs)

Genes:

RAD50:RAD50 double strand break repair protein [Gene - OMIM - HGNC]
TH2LCRR:T helper type 2 locus control region associated RNA [Gene - HGNC]
TH2-LCR:Th2 cytokine locus control region [Gene]

Variant type:

Deletion

Cytogenetic location:

5q31.1

Genomic location:

Preferred name:

NM_005732.4(RAD50):c.3489_3495del (p.Glu1164fs)

HGVS:

NC_000005.10:g.132638094_132638100del
NG_021151.2:g.86118_86124del
NG_042308.1:g.8932_8938del
NM_005732.4:c.3489_3495delMANE SELECT
NP_005723.2:p.Glu1164fs
LRG_312t1:c.3489_3495del
LRG_312:g.86118_86124del
LRG_312p1:p.Glu1164fs
NC_000005.9:g.131973786_131973792del
NG_021151.1:g.86171_86177del
NM_005732.3:c.3489_3495delAGAAATA
NR_132125.1:n.355_361del
NR_132126.1:n.340_346del

Protein change:

E1164fs

Links:

dbSNP: rs878854799

NCBI 1000 Genomes Browser:

rs878854799

Molecular consequence:

NM_005732.4:c.3489_3495del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_132125.1:n.355_361del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_132126.1:n.340_346del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000289057	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 8, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19409520, 28492532
SCV002612810	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 16, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000289057

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 8, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002612810

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 16, 2021)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder.

Waltes R, Kalb R, Gatei M, Kijas AW, Stumm M, Sobeck A, Wieland B, Varon R, Lerenthal Y, Lavin MF, Schindler D, Dörk T.

Am J Hum Genet. 2009 May;84(5):605-16. doi: 10.1016/j.ajhg.2009.04.010. Epub 2009 Apr 30.

PubMed [citation]

PMID:: 19409520
PMCID:: PMC2681000

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000289057.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Glu1164Glyfs*22) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 240238). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002612810.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The c.3489_3495delAGAAATA pathogenic mutation, located in coding exon 23 of the RAD50 gene, results from a deletion of 7 nucleotides at nucleotide positions 3489 to 3495, causing a translational frameshift with a predicted alternate stop codon (p.E1164Gfs*22). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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