NM_005732.4(RAD50):c.1722dup (p.Gln575fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 21, 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:: RCV000131751.14

Allele description [Variation Report for NM_005732.4(RAD50):c.1722dup (p.Gln575fs)]

NM_005732.4(RAD50):c.1722dup (p.Gln575fs)

Gene:

RAD50:RAD50 double strand break repair protein [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

5q31.1

Genomic location:

Preferred name:

NM_005732.4(RAD50):c.1722dup (p.Gln575fs)

HGVS:

NC_000005.10:g.132591963dup
NG_021151.2:g.39987dup
NM_005732.4:c.1722dupMANE SELECT
NP_005723.2:p.Gln575fs
LRG_312t1:c.1722dup
LRG_312:g.39987dup
LRG_312p1:p.Gln575fs
NC_000005.9:g.131927649_131927650insA
NC_000005.9:g.131927655dup
NG_021151.1:g.40040dup
NM_005732.3:c.1722dup
NM_005732.3:c.1722dupA
NM_005732.4:c.1722dupAMANE SELECT

Protein change:

Q575fs

Links:

dbSNP: rs587782543

NCBI 1000 Genomes Browser:

rs587782543

Molecular consequence:

NM_005732.4:c.1722dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV000186793	Ambry Genetics	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015))	Pathogenic (May 8, 2013)	germline	clinical testing	Citation Link,
SCV000663676	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 10, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000836404	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16385572, 19409520, 24763289, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186793

Ambry Genetics

criteria provided, single submitter

(Ambry Autosomal Dominant and X-Linked criteria (10/2015))

Pathogenic
(May 8, 2013)

germline

clinical testing

Citation Link,

SCV000663676

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 10, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000836404

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 21, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Evaluation of RAD50 in familial breast cancer predisposition.

Tommiska J, Seal S, Renwick A, Barfoot R, Baskcomb L, Jayatilake H, Bartkova J, Tallila J, Kaare M, Tamminen A, Heikkilä P, Evans DG, Eccles D, Aittomäki K, Blomqvist C, Bartek J, Stratton MR, Nevanlinna H, Rahman N.

Int J Cancer. 2006 Jun 1;118(11):2911-6.

PubMed [citation]

PMID:: 16385572

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

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000186793.5

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

Description

Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)

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

From Ambry Genetics, SCV000663676.4

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

Description

The c.1722dupA pathogenic mutation, located in coding exon 11 of the RAD50 gene, results from a duplication of A at nucleotide position 1722, causing a translational frameshift with a predicted alternate stop codon (p.Q575Tfs*3). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000836404.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Gln575Thrfs*3) 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 premature translational stop signal has been observed in individual(s) with hereditary cancer (PMID: 16385572, 19409520, 24763289). ClinVar contains an entry for this variant (Variation ID: 142556). 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

Last Updated: Sep 29, 2024

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