ClinVar Genomic variation as it relates to human health
NM_005732.4(RAD50):c.2840T>C (p.Ile947Thr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005732.4(RAD50):c.2840T>C (p.Ile947Thr)
Variation ID: 128013 Accession: VCV000128013.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q31.1 5: 132609127 (GRCh38) [ NCBI UCSC ] 5: 131944819 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 9, 2016 May 1, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005732.4:c.2840T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005723.2:p.Ile947Thr missense NC_000005.10:g.132609127T>C NC_000005.9:g.131944819T>C NG_021151.2:g.57151T>C LRG_312:g.57151T>C LRG_312t1:c.2840T>C LRG_312p1:p.Ile947Thr - Protein change
- I947T
- Other names
- p.I947T:ATT>ACT
- Canonical SPDI
- NC_000005.10:132609126:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD) 0.00009
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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RAD50 | - | - |
GRCh38 GRCh37 |
3732 | 4425 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000115949.22 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2023 | RCV000212922.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 10, 2023 | RCV001194193.2 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jul 9, 2016 | RCV000410140.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jul 09, 2016)
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criteria provided, single submitter
Method: clinical testing
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Nijmegen breakage syndrome-like disorder
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000488874.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Oct 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363538.2
First in ClinVar: Jun 22, 2020 Last updated: Nov 20, 2023 |
Comment:
Variant summary: RAD50 c.2840T>C (p.Ile947Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: RAD50 c.2840T>C (p.Ile947Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 247912 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), suggesting that the variant could be a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2840T>C has been reported in the literature in an individual affected with lung adenocarcinoma (Lu 2015), an individual with gastric cancer (Bruns_2022) and in an individual with an unspecified type of cancer from a cohort of patients who had a strong family history with at least two affected relatives (Sahin_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35250968, 26689913, 35089076). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(Jun 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149858.16
First in ClinVar: May 17, 2014 Last updated: Jul 22, 2023 |
Comment:
Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); In silico analysis supports that … (more)
Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26689913, Duzkale2020[article]) (less)
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Uncertain significance
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000254895.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 947 of the RAD50 protein (p.Ile947Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 947 of the RAD50 protein (p.Ile947Thr). This variant is present in population databases (rs150401251, gnomAD 0.01%). This missense change has been observed in individual(s) with lung adenocarcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 128013). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD50 protein function with a negative predictive value of 80%. 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. (less)
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Uncertain significance
(Mar 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000184404.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.I947T variant (also known as c.2840T>C), located in coding exon 18 of the RAD50 gene, results from a T to C substitution at nucleotide … (more)
The p.I947T variant (also known as c.2840T>C), located in coding exon 18 of the RAD50 gene, results from a T to C substitution at nucleotide position 2840. The isoleucine at codon 947 is replaced by threonine, an amino acid with similar properties. This amino acid position is well 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. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Nijmegen breakage syndrome-like disorder
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002075111.1
First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022 |
Comment:
Variant interpreted as Uncertain significance and reported on 03-25-2021 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the … (more)
Variant interpreted as Uncertain significance and reported on 03-25-2021 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Breast carcinoma (present) , Neoplasm of ovary (present) , Abnormality of eye movement (present) , Myopia (present)
Indication for testing: Diagnostic
Age: 60-69 years
Sex: female
Testing laboratory: PreventionGenetics,PreventionGenetics
Date variant was reported to submitter: 2021-03-25
Testing laboratory interpretation: Uncertain significance
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Common Variable Immunodeficiency-Associated Cancers: The Role of Clinical Phenotypes, Immunological and Genetic Factors. | Bruns L | Frontiers in immunology | 2022 | PMID: 35250968 |
New Perspectives on the Recurrent Monoallelic Germline Mutations of DNA Repair and Checkpoint Genes and Clinical Variability. | Sahin I | Genetic testing and molecular biomarkers | 2022 | PMID: 35089076 |
Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
Text-mined citations for rs150401251 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.