NM_005732.4(RAD50):c.2173C>T (p.Arg725Trp) AND Hereditary cancer-predisposing syndrome

Clinical significance:Uncertain significance (Last evaluated: Nov 2, 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:
RCV000131653.13

Allele description [Variation Report for NM_005732.4(RAD50):c.2173C>T (p.Arg725Trp)]

NM_005732.4(RAD50):c.2173C>T (p.Arg725Trp)

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.2173C>T (p.Arg725Trp)
HGVS:
  • NC_000005.10:g.132595776C>T
  • NG_021151.1:g.43853C>T
  • NG_021151.2:g.43800C>T
  • NM_005732.4:c.2173C>TMANE SELECT
  • NP_005723.2:p.Arg725Trp
  • LRG_312t1:c.2173C>T
  • LRG_312:g.43800C>T
  • LRG_312p1:p.Arg725Trp
  • NC_000005.9:g.131931468C>T
  • NM_005732.3:c.2173C>T
  • p.R725W
Protein change:
R725W
Links:
dbSNP: rs369560280
NCBI 1000 Genomes Browser:
rs369560280
Molecular consequence:
  • NM_005732.4:c.2173C>T - 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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000186680Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Dec 26, 2018)
germlineclinical testing

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

Citation Link,

SCV000289031Invitaecriteria provided, single submitter
Uncertain significance
(Nov 2, 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

Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study.

Damiola F, Pertesi M, Oliver J, Le Calvez-Kelm F, Voegele C, Young EL, Robinot N, Forey N, Durand G, Vallée MP, Tao K, Roane TC, Williams GJ, Hopper JL, Southey MC, Andrulis IL, John EM, Goldgar DE, Lesueur F, Tavtigian SV.

Breast Cancer Res. 2014 Jun 3;16(3):R58. doi: 10.1186/bcr3669.

PubMed [citation]
PMID:
24894818
PMCID:
PMC4229874

Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility.

Quezada Urban R, Díaz Velásquez CE, Gitler R, Rojo Castillo MP, Sirota Toporek M, Figueroa Morales A, Moreno García O, García Esquivel L, Torres Mejía G, Dean M, Delgado Enciso I, Ochoa Díaz López H, Rodríguez León F, Jan V, Garzón Barrientos VH, Ruiz Flores P, Espino Silva PK, Haro Santa Cruz J, Martínez Gregorio H, Rojas Jiménez EA, Romero Cruz LE, Méndez Catalá CF, et al.

Cancers (Basel). 2018 Sep 27;10(10). doi:pii: E361. 10.3390/cancers10100361.

PubMed [citation]
PMID:
30262796
PMCID:
PMC6211045
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000186680.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

The p.R725W variant (also known as c.2173C>T), located in coding exon 13 of the RAD50 gene, results from a C to T substitution at nucleotide position 2173. The arginine at codon 725 is replaced by tryptophan, an amino acid with dissimilar properties. In one study, this alteration was observed in 3/158 Hispanic individuals who were diagnosed with breast cancer before the age of 45, and was not seen in any controls matched for age and ethnicity (<span style="background-color:initial">Damiola F et al. Breast Cancer Res. 2014 Jun;16:R58). This alteration was also detected in a cohort of 327 Mexican patients with personal and/or family history suspicious for hereditary breast and ovarian cancer syndrome (Quezada Urban R et al. Cancers (Basel). 2018 Sep;10).This amino acid position is highly conserved through mammals but not in all 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, SCV000289031.8

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

Description

This sequence change replaces arginine with tryptophan at codon 725 of the RAD50 protein (p.Arg725Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs369560280, ExAC 0.1%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 24894818, 30262796). ClinVar contains an entry for this variant (Variation ID: 142505). 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: Possibly Damaging; 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: Jun 14, 2021

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