NM_005732.4(RAD50):c.3277C>T (p.Arg1093Ter) AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: Oct 14, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000575384.5

Allele description [Variation Report for NM_005732.4(RAD50):c.3277C>T (p.Arg1093Ter)]

NM_005732.4(RAD50):c.3277C>T (p.Arg1093Ter)

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.3277C>T (p.Arg1093Ter)
HGVS:
  • NC_000005.10:g.132618182C>T
  • NG_021151.1:g.66259C>T
  • NG_021151.2:g.66206C>T
  • NM_005732.4:c.3277C>TMANE SELECT
  • NP_005723.2:p.Arg1093Ter
  • LRG_312t1:c.3277C>T
  • LRG_312:g.66206C>T
  • LRG_312p1:p.Arg1093Ter
  • NC_000005.9:g.131953874C>T
  • NM_005732.3:c.3277C>T
Protein change:
R1093*; ARG1093TER
Links:
OMIM: 604040.0001; dbSNP: rs121912628
NCBI 1000 Genomes Browser:
rs121912628
Molecular consequence:
  • NM_005732.4:c.3277C>T - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000663600Ambry Geneticscriteria provided, single submitter
Pathogenic
(Feb 18, 2019)
germlineclinical testing

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

Citation Link,

SCV000829513Invitaecriteria provided, single submitter
Pathogenic
(Oct 14, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical 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 Ambry Genetics, SCV000663600.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

The p.R1093* pathogenic mutation (also known as c.3277C>T), located in coding exon 21 of the RAD50 gene, results from a C to T substitution at nucleotide position 3277. This changes the amino acid from an arginine to a stop codon within coding exon 21. This alteration was previously reported in the compound heterozygous state in a patient with a phenotype similar to Nijmegen breakage syndrome. Sequence analysis of cDNA revealed quasi-hemizygous expression of the other mutation, implying that the p.R1093* allele was subject to nonsense mediated decay (Waltes R et al. Am. J. Hum. Genet. 2009 May;84:605-16). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Invitae, SCV000829513.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Arg1093*) in the RAD50 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121912628, ExAC 0.001%). This variant has been observed in an individual affected with medulloblastoma (PMID: 19409520) and in an individual affected with Nijmegen breakage syndrome-like disorder who had a different pathogenic variant in RAD50 on the opposite chromosome (trans) (PMID: 19409520). ClinVar contains an entry for this variant (Variation ID: 5872). Loss-of-function variants in RAD50 are known to be pathogenic (PMID: 16385572, 19409520). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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