NM_005732.4(RAD50):c.2498_2499del (p.Gln833fs) AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: May 15, 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:
RCV000132534.9

Allele description [Variation Report for NM_005732.4(RAD50):c.2498_2499del (p.Gln833fs)]

NM_005732.4(RAD50):c.2498_2499del (p.Gln833fs)

Gene:
RAD50:RAD50 double strand break repair protein [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
5q31.1
Genomic location:
Preferred name:
NM_005732.4(RAD50):c.2498_2499del (p.Gln833fs)
HGVS:
  • NC_000005.10:g.132604020_132604021del
  • NG_021151.1:g.52097_52098del
  • NG_021151.2:g.52044_52045del
  • NM_005732.4:c.2498_2499delMANE SELECT
  • NP_005723.2:p.Gln833fs
  • LRG_312t1:c.2498_2499del
  • LRG_312:g.52044_52045del
  • LRG_312p1:p.Gln833fs
  • NC_000005.9:g.131939712_131939713del
  • NC_000005.9:g.131939712_131939713delAA
  • NM_005732.3:c.2498_2499del
  • NM_005732.3:c.2498_2499delAA
  • p.Q833RFS*11
Protein change:
Q833fs
Links:
dbSNP: rs587782895
NCBI 1000 Genomes Browser:
rs587782895
Molecular consequence:
  • NM_005732.4:c.2498_2499del - frameshift variant - [Sequence Ontology: SO:0001589]
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
SCV000187631Ambry Geneticscriteria provided, single submitter
Pathogenic
(Dec 6, 2017)
germlineclinical testing

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

Citation Link,

SCV000548004Invitaecriteria provided, single submitter
Pathogenic
(May 15, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Multiple gene sequencing for risk assessment in patients with early-onset or familial breast cancer.

Lin PH, Kuo WH, Huang AC, Lu YS, Lin CH, Kuo SH, Wang MY, Liu CY, Cheng FT, Yeh MH, Li HY, Yang YH, Hsu YH, Fan SC, Li LY, Yu SL, Chang KJ, Chen PL, Ni YH, Huang CS.

Oncotarget. 2016 Feb 16;7(7):8310-20. doi: 10.18632/oncotarget.7027.

PubMed [citation]
PMID:
26824983
PMCID:
PMC4884994

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
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000187631.6

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

Description

The c.2498_2499delAA pathogenic mutation, located in coding exon 15 of the RAD50 gene, results from a deletion of two nucleotides at nucleotide positions 2498 to 2499, causing a translational frameshift with a predicted alternate stop codon (p.Q833Rfs*11). This pathogenic mutation was observed in a study of high-risk breast cancer patients who underwent multi-gene panel testing (Lin PH et al. Oncotarget 2016 Feb;7(7):8310-20). 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, SCV000548004.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Gln833Argfs*11) in the RAD50 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with breast cancer (PMID: 26824983). ClinVar contains an entry for this variant (Variation ID: 143015). 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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