NM_005732.4(RAD50):c.2840T>C (p.Ile947Thr) AND Hereditary cancer-predisposing syndrome

Clinical significance:Uncertain significance (Last evaluated: Oct 30, 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:
RCV000115949.16

Allele description [Variation Report for NM_005732.4(RAD50):c.2840T>C (p.Ile947Thr)]

NM_005732.4(RAD50):c.2840T>C (p.Ile947Thr)

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.2840T>C (p.Ile947Thr)
Other names:
p.I947T:ATT>ACT
HGVS:
  • NC_000005.10:g.132609127T>C
  • NG_021151.1:g.57204T>C
  • NG_021151.2:g.57151T>C
  • NM_005732.4:c.2840T>CMANE SELECT
  • NP_005723.2:p.Ile947Thr
  • LRG_312t1:c.2840T>C
  • LRG_312:g.57151T>C
  • LRG_312p1:p.Ile947Thr
  • NC_000005.9:g.131944819T>C
  • NM_005732.3:c.2840T>C
  • p.I947T
Protein change:
I947T
Links:
dbSNP: rs150401251
NCBI 1000 Genomes Browser:
rs150401251
Molecular consequence:
  • NM_005732.4:c.2840T>C - missense variant - [Sequence Ontology: SO:0001583]
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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000184404Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Nov 1, 2018)
germlineclinical testing

Citation Link,

SCV000254895Invitaecriteria provided, single submitter
Uncertain significance
(Oct 30, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Patterns and functional implications of rare germline variants across 12 cancer types.

Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, Huang KL, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C, Bharadwaj M, Koboldt DC, et al.

Nat Commun. 2015 Dec 22;6:10086. doi: 10.1038/ncomms10086.

PubMed [citation]
PMID:
26689913
PMCID:
PMC4703835

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, SCV000184404.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The p.I947T variant (also known as c.2840T>C), located in coding exon 18 of the RAD50 gene, results from a T to C substitution at nucleotide position 2840. The isoleucine at codon 947 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

From Invitae, SCV000254895.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces isoleucine with threonine at codon 947 of the RAD50 protein (p.Ile947Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs150401251, ExAC 0.009%). This variant has been reported in the literature in an individual affected with lung adenocarcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 128013). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Nov 27, 2021

Support Center