This sequence change creates a premature translational stop signal (p.Tyr625*) in the RAD50 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs149201802, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with pancreatic and breast cancer (PMID: 18281469, 25452441). ClinVar contains an entry for this variant (Variation ID: 220719). Studies have shown that this premature translational stop signal results in skipping of exon 12 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_005732.4(RAD50):c.1875C>G (p.Tyr625Ter)
Germline
Classification
Help
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.
(10)
Help
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.
Pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005732.4(RAD50):c.1875C>G (p.Tyr625Ter)
Variation ID: 220719 Accession: VCV000220719.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q31.1 5: 132594950 (GRCh38) [ NCBI UCSC ] 5: 131930642 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 6, 2017 Jun 17, 2024 Feb 16, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005732.4:c.1875C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005723.2:p.Tyr625Ter nonsense NC_000005.10:g.132594950C>G NC_000005.9:g.131930642C>G NG_021151.2:g.42974C>G LRG_312:g.42974C>G LRG_312t1:c.1875C>G LRG_312p1:p.Tyr625Ter - Protein change
- Y625*
- Other names
- -
- Canonical SPDI
- NC_000005.10:132594949:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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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0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00006
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| RAD50 | - | - |
GRCh38 GRCh37 |
3781 | 4478 | |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 30, 2024 | RCV000205188.17 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 16, 2024 | RCV000411352.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 11, 2019 | RCV001270999.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 23, 2022 | RCV003477703.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 17, 2022 | RCV002280874.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 13, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Nijmegen breakage syndrome-like disorder
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000489273.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000261499.12
First in ClinVar: Feb 02, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr625*) in the RAD50 gene. RNA analysis indicates that this premature translational stop signal induces altered … (more)
This sequence change creates a premature translational stop signal (p.Tyr625*) in the RAD50 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs149201802, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with pancreatic and breast cancer (PMID: 18281469, 25452441). ClinVar contains an entry for this variant (Variation ID: 220719). Studies have shown that this premature translational stop signal results in skipping of exon 12 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Sep 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000273485.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.Y625* pathogenic mutation (also known as c.1875C>G), located in coding exon 12 of the RAD50 gene, results from a C to G substitution at … (more)
The p.Y625* pathogenic mutation (also known as c.1875C>G), located in coding exon 12 of the RAD50 gene, results from a C to G substitution at nucleotide position 1875. This changes the amino acid from a tyrosine to a stop codon within coding exon 12. This alteration has been detected in 2/1824 patients with triple-negative breast cancer who were unselected for a family history of breast or ovarian cancer (Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11). This variant was also reported in 2/1313 early-onset breast cancer cases and 0/1123 population controls (Damiola F et al. Breast Cancer Res, 2014 Jun;16:R58). In addition, this alteration was identified in a 77 year old woman with pancreatic ductal adenocarcinoma and non-Hodgkin's lymphoma and in a male diagnosed with pancreatic cancer (Yurgelun MB et al. Genet Med, 2019 01;21:213-223; Wang X et al. Cancer Res., 2008 Feb;68:971-5). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Jan 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000821772.2
First in ClinVar: Oct 10, 2018 Last updated: Apr 22, 2020 |
Comment:
This variant is a single amino acid change from Tytosine to a premature translational stop signal at codon 625 of the RAD50 protein. This is … (more)
This variant is a single amino acid change from Tytosine to a premature translational stop signal at codon 625 of the RAD50 protein. This is expected to result in an absent or disrupted protein product. Truncating variants in RAD50 are known to be pathogenic (PMID: 19409520, 16385572).This variant has been described in the international literature in individuals affected with pancreatic and breast cancer (PMID: 18281469, 25452441) and in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 220719). . (less)
|
|
|
Pathogenic
(Jan 13, 2022)
|
criteria provided, single submitter
Method: curation
|
Nijmegen breakage syndrome-like disorder
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002538462.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The RAD50 c.1875C>G (p.Y625X) variant has been reported in heterozygosity in at least 5 individuals with breast or pancreatic cancer (PMID: 25452441, 31159747, 29961768, 18281469). … (more)
The RAD50 c.1875C>G (p.Y625X) variant has been reported in heterozygosity in at least 5 individuals with breast or pancreatic cancer (PMID: 25452441, 31159747, 29961768, 18281469). This nonsense variant creates a premature stop codon at residue 625 of the RAD50 protein. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). Loss of function variants in RAD50 are known to be pathogenic (PMID: 19409520, 16385572). This variant was observed in 20/35426 chromosomes in the Latino population, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 220719). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
|
|
|
|
Pathogenic
(Nov 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004219295.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
This nonsense variant causes the premature termination of RAD50 protein synthesis. The frequency of this variant in the general population, 0.00056 (20/35426 chromosomes, http://gnomad.broadinstitute.org), is … (more)
This nonsense variant causes the premature termination of RAD50 protein synthesis. The frequency of this variant in the general population, 0.00056 (20/35426 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 25452441 (2015)) and pancreatic cancer (PMID: 29961768 (2019)). It has also been reported in an individual with personal and/or family history of breast and/or ovarian cancer (PMID:31159747 (2019)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Nijmegen breakage syndrome-like disorder
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019604.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Feb 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Nijmegen breakage syndrome-like disorder
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001525046.2
First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jun 11, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: yes
Allele origin:
germline
|
CZECANCA consortium
Accession: SCV001451811.1
First in ClinVar: Dec 24, 2020 Last updated: Dec 24, 2020 |
Number of individuals with the variant: 1
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
|
|
|
Likely pathogenic
(May 17, 2022)
|
no assertion criteria provided
Method: case-control
|
Hepatocellular carcinoma
Affected status: yes
Allele origin:
germline
|
CZECANCA consortium
Accession: SCV002569173.1
First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022 |
|
Comment:
Comment:
The p.Y625* pathogenic mutation (also known as c.1875C>G), located in coding exon 12 of the RAD50 gene, results from a C to G substitution at nucleotide position 1875. This changes the amino acid from a tyrosine to a stop codon within coding exon 12. This alteration has been detected in 2/1824 patients with triple-negative breast cancer who were unselected for a family history of breast or ovarian cancer (Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11). This variant was also reported in 2/1313 early-onset breast cancer cases and 0/1123 population controls (Damiola F et al. Breast Cancer Res, 2014 Jun;16:R58). In addition, this alteration was identified in a 77 year old woman with pancreatic ductal adenocarcinoma and non-Hodgkin's lymphoma and in a male diagnosed with pancreatic cancer (Yurgelun MB et al. Genet Med, 2019 01;21:213-223; Wang X et al. Cancer Res., 2008 Feb;68:971-5). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is a single amino acid change from Tytosine to a premature translational stop signal at codon 625 of the RAD50 protein. This is expected to result in an absent or disrupted protein product. Truncating variants in RAD50 are known to be pathogenic (PMID: 19409520, 16385572).This variant has been described in the international literature in individuals affected with pancreatic and breast cancer (PMID: 18281469, 25452441) and in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 220719). .
Comment:
This nonsense variant causes the premature termination of RAD50 protein synthesis. The frequency of this variant in the general population, 0.00056 (20/35426 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 25452441 (2015)) and pancreatic cancer (PMID: 29961768 (2019)). It has also been reported in an individual with personal and/or family history of breast and/or ovarian cancer (PMID:31159747 (2019)). Based on the available information, this variant is classified as pathogenic.
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. |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr625*) in the RAD50 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs149201802, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with pancreatic and breast cancer (PMID: 18281469, 25452441). ClinVar contains an entry for this variant (Variation ID: 220719). Studies have shown that this premature translational stop signal results in skipping of exon 12 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Y625* pathogenic mutation (also known as c.1875C>G), located in coding exon 12 of the RAD50 gene, results from a C to G substitution at nucleotide position 1875. This changes the amino acid from a tyrosine to a stop codon within coding exon 12. This alteration has been detected in 2/1824 patients with triple-negative breast cancer who were unselected for a family history of breast or ovarian cancer (Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11). This variant was also reported in 2/1313 early-onset breast cancer cases and 0/1123 population controls (Damiola F et al. Breast Cancer Res, 2014 Jun;16:R58). In addition, this alteration was identified in a 77 year old woman with pancreatic ductal adenocarcinoma and non-Hodgkin's lymphoma and in a male diagnosed with pancreatic cancer (Yurgelun MB et al. Genet Med, 2019 01;21:213-223; Wang X et al. Cancer Res., 2008 Feb;68:971-5). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is a single amino acid change from Tytosine to a premature translational stop signal at codon 625 of the RAD50 protein. This is expected to result in an absent or disrupted protein product. Truncating variants in RAD50 are known to be pathogenic (PMID: 19409520, 16385572).This variant has been described in the international literature in individuals affected with pancreatic and breast cancer (PMID: 18281469, 25452441) and in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 220719). .
Comment:
This nonsense variant causes the premature termination of RAD50 protein synthesis. The frequency of this variant in the general population, 0.00056 (20/35426 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 25452441 (2015)) and pancreatic cancer (PMID: 29961768 (2019)). It has also been reported in an individual with personal and/or family history of breast and/or ovarian cancer (PMID:31159747 (2019)). Based on the available information, this variant is classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
| Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
| Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. | Yurgelun MB | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29961768 |
| Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. | Couch FJ | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25452441 |
| 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 |
| Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder. | Waltes R | American journal of human genetics | 2009 | PMID: 19409520 |
| Mutational analysis of thirty-two double-strand DNA break repair genes in breast and pancreatic cancers. | Wang X | Cancer research | 2008 | PMID: 18281469 |
| Evaluation of RAD50 in familial breast cancer predisposition. | Tommiska J | International journal of cancer | 2006 | PMID: 16385572 |
Text-mined citations for rs149201802 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.