NM_005732.4(RAD50):c.1114C>T (p.Gln372Ter) AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: Oct 29, 2018)

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:
RCV000566508.2

Allele description [Variation Report for NM_005732.4(RAD50):c.1114C>T (p.Gln372Ter)]

NM_005732.4(RAD50):c.1114C>T (p.Gln372Ter)

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.1114C>T (p.Gln372Ter)
HGVS:
  • NC_000005.10:g.132588749C>T
  • NG_021151.1:g.36826C>T
  • NG_021151.2:g.36773C>T
  • NM_005732.4:c.1114C>TMANE SELECT
  • NP_005723.2:p.Gln372Ter
  • LRG_312t1:c.1114C>T
  • LRG_312:g.36773C>T
  • LRG_312p1:p.Gln372Ter
  • NC_000005.8:g.131952340C>T
  • NC_000005.9:g.131924441C>T
  • NM_005732.3:c.1114C>T
Protein change:
Q372*
Links:
dbSNP: rs104895046
NCBI 1000 Genomes Browser:
rs104895046
Molecular consequence:
  • NM_005732.4:c.1114C>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
SCV000671822Ambry Geneticscriteria provided, single submitter
Pathogenic
(Nov 1, 2016)
germlineclinical testing

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

Citation Link,

SCV000956155Invitaecriteria provided, single submitter
Pathogenic
(Oct 29, 2018)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID.

Offer SM, Pan-Hammarström Q, Hammarström L, Harris RS.

PLoS One. 2010 Aug 18;5(8):e12260. doi: 10.1371/journal.pone.0012260.

PubMed [citation]
PMID:
20805886
PMCID:
PMC2923613

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Ambry Genetics, SCV000671822.3

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

Description

The p.Q372* pathogenic mutation (also known as c.1114C>T), located in coding exon 8 of the RAD50 gene, results from a C to T substitution at nucleotide position 1114. This changes the amino acid from a glutamine to a stop codon within coding exon 8. One study assessed the role of this mutation in the primary antibody deficiency syndromes IgAD and CVID, and found that cell lines harboring this mutation displayed an impaired ability of the MRN complex to repair ionizing radiation-induced DNA double strand breaks, suggesting an increased sensitivity to ionizing radiation (Offer SM et al. PLoS ONE, 2010 Aug;5:e12260). 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, SCV000956155.1

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

Description

This sequence change creates a premature translational stop signal (p.Gln372*) in the RAD50 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs104895046, ExAC 0.002%). This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 126999). Experimental studies have shown that this nonsense change results in increased sensitivity to ionizing radiation compared to the wild-type controls (PMID: 20805886). 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: Jan 25, 2021

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