NM_005732.4(RAD50):c.1963C>T (p.Gln655Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 9, 2021
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:: RCV001039714.8

Allele description [Variation Report for NM_005732.4(RAD50):c.1963C>T (p.Gln655Ter)]

NM_005732.4(RAD50):c.1963C>T (p.Gln655Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

5q31.1

Genomic location:

Preferred name:

NM_005732.4(RAD50):c.1963C>T (p.Gln655Ter)

HGVS:

NC_000005.10:g.132595038C>T
NG_021151.2:g.43062C>T
NM_005732.4:c.1963C>TMANE SELECT
NP_005723.2:p.Gln655Ter
LRG_312t1:c.1963C>T
LRG_312:g.43062C>T
LRG_312p1:p.Gln655Ter
NC_000005.9:g.131930730C>T
NG_021151.1:g.43115C>T
NM_005732.3:c.1963C>T

Protein change:

Q655*

Links:

dbSNP: rs1750765838

NCBI 1000 Genomes Browser:

rs1750765838

Molecular consequence:

NM_005732.4:c.1963C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001203257	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 9, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16385572, 19409520, 28492532
SCV002722228	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 3, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001203257

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 9, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002722228

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 3, 2020)

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

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 (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001203257.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 838210). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln655*) 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: 16385572, 19409520).

#	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, SCV002722228.2

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

Description

The p.Q655* pathogenic mutation (also known as c.1963C>T), located in coding exon 12 of the RAD50 gene, results from a C to T substitution at nucleotide position 1963. This changes the amino acid from a glutamine to a stop codon within coding exon 12. 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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