NM_005732.4(RAD50):c.1721A>G (p.Lys574Arg) AND Hereditary cancer-predisposing syndrome

Clinical significance:Uncertain significance (Last evaluated: Jul 9, 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:
RCV000563257.4

Allele description [Variation Report for NM_005732.4(RAD50):c.1721A>G (p.Lys574Arg)]

NM_005732.4(RAD50):c.1721A>G (p.Lys574Arg)

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.1721A>G (p.Lys574Arg)
HGVS:
  • NC_000005.10:g.132591962A>G
  • NG_021151.1:g.40039A>G
  • NG_021151.2:g.39986A>G
  • NM_005732.4:c.1721A>GMANE SELECT
  • NP_005723.2:p.Lys574Arg
  • LRG_312t1:c.1721A>G
  • LRG_312:g.39986A>G
  • LRG_312p1:p.Lys574Arg
  • NC_000005.9:g.131927654A>G
  • NM_005732.3:c.1721A>G
Protein change:
K574R
Links:
dbSNP: rs1386858430
NCBI 1000 Genomes Browser:
rs1386858430
Molecular consequence:
  • NM_005732.4:c.1721A>G - 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
SCV000667027Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Jul 9, 2020)
germlineclinical testing

Citation Link,

SCV001205429Invitaecriteria provided, single submitter
Uncertain significance
(Mar 29, 2019)
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

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, SCV000667027.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The p.K574R variant (also known as c.1721A>G), located in coding exon 11 of the RAD50 gene, results from an A to G substitution at nucleotide position 1721. The lysine at codon 574 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, arginine is the reference amino acid in other 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, SCV001205429.2

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

Description

This sequence change replaces lysine with arginine at codon 574 of the RAD50 protein (p.Lys574Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 482106). 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

Last Updated: Nov 27, 2021

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