NM_005732.4(RAD50):c.217G>A (p.Ala73Thr) AND Hereditary cancer-predisposing syndrome

Clinical significance:Uncertain significance (Last evaluated: Oct 24, 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:
RCV000220496.8

Allele description [Variation Report for NM_005732.4(RAD50):c.217G>A (p.Ala73Thr)]

NM_005732.4(RAD50):c.217G>A (p.Ala73Thr)

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.217G>A (p.Ala73Thr)
HGVS:
  • NC_000005.10:g.132575780G>A
  • NG_021151.1:g.23857G>A
  • NG_021151.2:g.23804G>A
  • NM_005732.4:c.217G>AMANE SELECT
  • NP_005723.2:p.Ala73Thr
  • LRG_312t1:c.217G>A
  • LRG_312:g.23804G>A
  • LRG_312p1:p.Ala73Thr
  • NC_000005.9:g.131911472G>A
  • NM_005732.3:c.217G>A
Protein change:
A73T
Links:
dbSNP: rs371122101
NCBI 1000 Genomes Browser:
rs371122101
Molecular consequence:
  • NM_005732.4:c.217G>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
SCV000273680Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Jan 11, 2019)
germlineclinical testing

Citation Link,

SCV000548054Invitaecriteria provided, single submitter
Uncertain significance
(Oct 24, 2020)
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, SCV000273680.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The p.A73T variant (also known as c.217G>A), located in coding exon 3 of the RAD50 gene, results from a G to A substitution at nucleotide position 217. The alanine at codon 73 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly 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, SCV000548054.7

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

Description

This sequence change replaces alanine with threonine at codon 73 of the RAD50 protein (p.Ala73Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs371122101, ExAC 0.01%) but has not been reported in the literature in individuals with a RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 230217). 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, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. 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: Oct 8, 2021

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