ClinVar Genomic variation as it relates to human health
NM_005732.4(RAD50):c.379G>A (p.Val127Ile)
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.
Uncertain significance(3); Benign(5); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005732.4(RAD50):c.379G>A (p.Val127Ile)
Variation ID: 128023 Accession: VCV000128023.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q31.1 5: 132579330 (GRCh38) [ NCBI UCSC ] 5: 131915022 (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 Jun 1, 2016 Oct 8, 2024 May 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005732.4:c.379G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005723.2:p.Val127Ile missense NC_000005.10:g.132579330G>A NC_000005.9:g.131915022G>A NG_021151.2:g.27354G>A LRG_312:g.27354G>A LRG_312t1:c.379G>A LRG_312p1:p.Val127Ile Q92878:p.Val127Ile - Protein change
- V127I
- Other names
- p.V127I:GTC>ATC
- Canonical SPDI
- NC_000005.10:132579329:G:A
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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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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
The Genome Aggregation Database (gnomAD) 0.00146
Trans-Omics for Precision Medicine (TOPMed) 0.00155
Exome Aggregation Consortium (ExAC) 0.00165
The Genome Aggregation Database (gnomAD), exomes 0.00165
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00177
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 |
3780 | 4477 |
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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Benign (2) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000115960.24 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 9, 2020 | RCV000409627.6 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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May 1, 2024 | RCV000590280.18 | |
Benign (1) |
criteria provided, single submitter
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Jun 22, 2021 | RCV001818283.4 |
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 07, 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: SCV000488865.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009648.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Benign
(Jul 11, 2014)
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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: SCV000183854.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Benign
(Aug 29, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698654.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The RAD50 c.379G>A (p.Val127Ile) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant. … (more)
Variant summary: The RAD50 c.379G>A (p.Val127Ile) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant. This variant was found in 205/124248 control chromosomes (1 homozygote) at a frequency of 0.0016499, which is approximately 26 times the estimated maximal expected allele frequency of a pathogenic RAD50 variant (0.0000625), suggesting this variant is likely a benign polymorphism. This variant has been reported from case-control studies in literature. In a large case-control study, this variant was not associated with increased risk for breast cancer (Haiman_2013). 1/3 clinical diagnostic laboratories in ClinVar has classified this variant as likely benign. Taken together, this variant is classified as Benign. (less)
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Uncertain significance
(Feb 21, 2014)
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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: SCV000149869.11
First in ClinVar: May 17, 2014 Last updated: Apr 17, 2019 |
Comment:
RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.379G>A at … (more)
RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.379G>A at the cDNA level and p.Val127Ile (V127I) at the protein level, and results in the change of a Valine to a Isoleucine (GTC>ATC). RAD50 Val127Ile has been reported in two individuals with breast cancer in British studies and in two individuals with laryngeal cancer in a Polish study, but was also detected in at least five healthy controls (Tommiska 2006, Mosor 2010, Mosor 2013, Ziolkowska-Suchanek 2013). RAD50 Val127Ile was observed with an allele frequency of 0.1% in 1000 Genomes and at 0.2% and 0.05% in European and African Americans in the NHLBI Exome Sequencing Project respectively, indicating it is not a common benign variant in these populations. This variant is a conservative substitution of one neutral non-polar amino acid for another, altering a position that is highly conserved throughout evolution, and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. At a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear. (less)
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Benign
(Jun 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002069722.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Benign
(Oct 09, 2020)
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criteria provided, single submitter
Method: curation
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Nijmegen breakage syndrome-like disorder
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002538517.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Benign
(Jan 31, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000253469.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
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Likely benign
(May 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004161371.9
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
RAD50: BS2
Number of individuals with the variant: 6
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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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Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study. | Damiola F | Breast cancer research : BCR | 2014 | PMID: 24894818 |
Integrated analysis of germline and somatic variants in ovarian cancer. | Kanchi KL | Nature communications | 2014 | PMID: 24448499 |
Germline variants in MRE11/RAD50/NBN complex genes in childhood leukemia. | Mosor M | BMC cancer | 2013 | PMID: 24093751 |
The MRN protein complex genes: MRE11 and RAD50 and susceptibility to head and neck cancers. | Ziółkowska-Suchanek I | Molecular cancer | 2013 | PMID: 24079363 |
Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population. | Haiman CA | PLoS genetics | 2013 | PMID: 23555315 |
RAD50 gene mutations are not likely a risk factor for breast cancer in Poland. | Mosor M | Breast cancer research and treatment | 2010 | PMID: 20571869 |
Evaluation of RAD50 in familial breast cancer predisposition. | Tommiska J | International journal of cancer | 2006 | PMID: 16385572 |
Text-mined citations for rs28903086 ...
HelpRecord last updated Oct 08, 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.