NM_005732.4(RAD50):c.2177G>A (p.Arg726His) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(2) (Last evaluated: Oct 27, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000115937.17

Allele description [Variation Report for NM_005732.4(RAD50):c.2177G>A (p.Arg726His)]

NM_005732.4(RAD50):c.2177G>A (p.Arg726His)

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.2177G>A (p.Arg726His)
Other names:
p.R726H:CGT>CAT
HGVS:
  • NC_000005.10:g.132595780G>A
  • NG_021151.1:g.43857G>A
  • NG_021151.2:g.43804G>A
  • NM_005732.4:c.2177G>AMANE SELECT
  • NP_005723.2:p.Arg726His
  • LRG_312t1:c.2177G>A
  • LRG_312:g.43804G>A
  • LRG_312p1:p.Arg726His
  • NC_000005.9:g.131931472G>A
  • NM_005732.3:c.2177G>A
  • p.R726H
Protein change:
R726H
Links:
dbSNP: rs28903092
NCBI 1000 Genomes Browser:
rs28903092
Molecular consequence:
  • NM_005732.4:c.2177G>A - 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
SCV000184077Ambry Geneticscriteria provided, single submitter
Likely benign
(Mar 24, 2020)
germlineclinical testing

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

Citation Link,

SCV000261760Invitaecriteria provided, single submitter
Uncertain significance
(Oct 27, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000822148GeneKor MSAcriteria provided, single submitter
Uncertain significance
(Aug 1, 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
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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

Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer.

Maxwell KN, Wubbenhorst B, D'Andrea K, Garman B, Long JM, Powers J, Rathbun K, Stopfer JE, Zhu J, Bradbury AR, Simon MS, DeMichele A, Domchek SM, Nathanson KL.

Genet Med. 2015 Aug;17(8):630-8. doi: 10.1038/gim.2014.176. Epub 2014 Dec 11.

PubMed [citation]
PMID:
25503501
PMCID:
PMC4465412
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000184077.6

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

Description

In silico models in agreement (benign);Insufficient or conflicting evidence;No disease association in small case-control study;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene

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

From Invitae, SCV000261760.9

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

Description

This sequence change replaces arginine with histidine at codon 726 of the RAD50 protein (p.Arg726His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs28903092, ExAC 0.06%). This variant has been reported in individuals affected with breast cancer (PMID: 16385572, 25503501). ClinVar contains an entry for this variant (Variation ID: 128001). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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

From GeneKor MSA, SCV000822148.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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