NM_005732.4(RAD50):c.323A>G (p.Lys108Arg) AND Hereditary cancer-predisposing syndrome

Clinical significance:Uncertain significance (Last evaluated: Oct 7, 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:
RCV000198855.9

Allele description [Variation Report for NM_005732.4(RAD50):c.323A>G (p.Lys108Arg)]

NM_005732.4(RAD50):c.323A>G (p.Lys108Arg)

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.323A>G (p.Lys108Arg)
HGVS:
  • NC_000005.10:g.132575886A>G
  • NG_021151.1:g.23963A>G
  • NG_021151.2:g.23910A>G
  • NM_005732.4:c.323A>GMANE SELECT
  • NP_005723.2:p.Lys108Arg
  • LRG_312t1:c.323A>G
  • LRG_312:g.23910A>G
  • LRG_312p1:p.Lys108Arg
  • NC_000005.9:g.131911578A>G
  • NM_005732.3:c.323A>G
Protein change:
K108R
Links:
dbSNP: rs542347773
NCBI 1000 Genomes Browser:
rs542347773
Molecular consequence:
  • NM_005732.4:c.323A>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
SCV000254897Invitaecriteria provided, single submitter
Uncertain significance
(Oct 7, 2020)
germlineclinical testing

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

SCV000663597Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Apr 3, 2019)
germlineclinical testing

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

Citation Link

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

The frequency of cancer predisposition gene mutations in hereditary breast and ovarian cancer patients in Taiwan: From BRCA1/2 to multi-gene panels.

Sung PL, Wen KC, Chen YJ, Chao TC, Tsai YF, Tseng LM, Qiu JT, Chao KC, Wu HH, Chuang CM, Wang PH, Huang CF.

PLoS One. 2017;12(9):e0185615. doi: 10.1371/journal.pone.0185615.

PubMed [citation]
PMID:
28961279
PMCID:
PMC5621677

Details of each submission

From Invitae, SCV000254897.8

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

Description

This sequence change replaces lysine with arginine at codon 108 of the RAD50 protein (p.Lys108Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs542347773, ExAC 0.06%). This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 216628). 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: Tolerated; 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

From Ambry Genetics, SCV000663597.3

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

Description

The p.K108R variant (also known as c.323A>G), located in coding exon 3 of the RAD50 gene, results from an A to G substitution at nucleotide position 323. The lysine at codon 108 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in a cancer-free individual whose mother was diagnosed with breast cancer at age 30 from a cohort of 272 Taiwanese hereditary breast and/or ovarian cancer patients (Sung PL et al. PLoS ONE, 2017 Sep;12:e0185615). 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

Last Updated: Jun 14, 2021

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