NM_005732.4(RAD50):c.2165dup (p.Glu723fs) AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: Oct 21, 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:
RCV000129381.15

Allele description [Variation Report for NM_005732.4(RAD50):c.2165dup (p.Glu723fs)]

NM_005732.4(RAD50):c.2165dup (p.Glu723fs)

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.2165dup (p.Glu723fs)
HGVS:
  • NC_000005.10:g.132595768dup
  • NG_021151.1:g.43845dup
  • NG_021151.2:g.43792dup
  • NM_005732.4:c.2165dupMANE SELECT
  • NP_005723.2:p.Glu723fs
  • LRG_312t1:c.2165dup
  • LRG_312:g.43792dup
  • LRG_312p1:p.Glu723fs
  • NC_000005.9:g.131931451_131931452insA
  • NC_000005.9:g.131931460dup
  • NM_005732.3:c.2165dupA
  • NM_005732.4:c.2157dupAMANE SELECT
  • p.E723Gfs*5
Protein change:
E723fs
Links:
dbSNP: rs397507178
NCBI 1000 Genomes Browser:
rs397507178
Molecular consequence:
  • NM_005732.4:c.2165dup - 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
SCV000184147Ambry Geneticscriteria provided, single submitter
Pathogenic
(Dec 21, 2018)
germlineclinical testing

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

Citation Link,

SCV000255302Invitaecriteria provided, single submitter
Pathogenic
(Oct 21, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.

Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, Olson JE, Godwin AK, Pankratz VS, Olswold C, Slettedahl S, Hallberg E, Guidugli L, Davila JI, Beckmann MW, Janni W, Rack B, Ekici AB, Slamon DJ, Konstantopoulou I, Fostira F, Vratimos A, et al.

J Clin Oncol. 2015 Feb 1;33(4):304-11. doi: 10.1200/JCO.2014.57.1414. Epub 2014 Dec 1.

PubMed [citation]
PMID:
25452441
PMCID:
PMC4302212

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
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000184147.6

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

Description

The c.2165dupA pathogenic mutation, located in coding exon 13 of the RAD50 gene, results from a duplication of A at nucleotide position 2165, causing a translational frameshift with a predicted alternate stop codon (p.E723Gfs*5). This alteration (designated as c.2157dupA) was reported in a cohort of 133 patients with early-onset or familial breast cancer (Lin PH et al. Oncotarget. 2016 Feb;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, SCV000255302.10

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Glu723Glyfs*5) in the RAD50 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported in individuals with breast cancer (PMID: 25452441, 26824983). This variant is also known as c.2157dupA in the literature. ClinVar contains an entry for this variant (Variation ID: 141045). 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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