ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.7232A>C (p.Lys2411Thr)
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_000059.4(BRCA2):c.7232A>C (p.Lys2411Thr)
Variation ID: 52294 Accession: VCV000052294.42
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32355085 (GRCh38) [ NCBI UCSC ] 13: 32929222 (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 Apr 1, 2014 Apr 15, 2024 Jun 18, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.7232A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Lys2411Thr missense NC_000013.11:g.32355085A>C NC_000013.10:g.32929222A>C NG_012772.3:g.44606A>C LRG_293:g.44606A>C LRG_293t1:c.7232A>C LRG_293p1:p.Lys2411Thr U43746.1:n.7460A>C - Protein change
- K2411T
- Other names
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- Canonical SPDI
- NC_000013.11:32355084:A: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
The Genome Aggregation Database (gnomAD) 0.00001
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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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18445 | 18602 |
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 (5) |
reviewed by expert panel
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Jun 18, 2019 | RCV000113734.18 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Feb 2, 2022 | RCV000163022.14 | |
Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000590755.25 | |
Benign (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV001084424.13 | |
Benign (4) |
criteria provided, multiple submitters, no conflicts
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Jul 18, 2022 | RCV001723635.13 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 18, 2019 | RCV003925003.1 |
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. |
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Benign
(Jun 18, 2019)
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reviewed by expert panel
Method: curation
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV001161531.2
First in ClinVar: Feb 16, 2020 Last updated: Jan 07, 2023 |
Comment:
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on … (more)
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00026 (less)
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Benign
(Jul 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743329.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Likely benign
(Feb 02, 2022)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002531844.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
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Benign
(Jul 18, 2022)
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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: SCV000695050.2
First in ClinVar: Mar 17, 2018 Last updated: Sep 17, 2022 |
Comment:
Variant summary: BRCA2 c.7232A>C (p.Lys2411Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: BRCA2 c.7232A>C (p.Lys2411Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251296 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (6e-05 vs 0.00075), allowing no conclusion about variant significance. c.7232A>C has been reported in the literature in individuals undergoing testing for breast cancer (example, Borg_2010, Capanu_2011, Laitman_2012, van der Hout_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multifactorial probability studies have reported a neutral impact (example, Easton_2007, Lindor_2012). At-least two co-occurrences with another pathogenic variant(s) have been reported in the UMD and BIC databases (BRCA1 c.5145del, p.Tyr1716fs), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function (example, Guidugli_2012, Ikegami_2020). These results showed no damaging effect of this variant on homology directed repair (HDR) activity. Multiple clinical diagnostic laboratories and an expett panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Feb 10, 2017)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000683857.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
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Benign
(Jun 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000887906.4
First in ClinVar: Mar 17, 2018 Last updated: Dec 31, 2022 |
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Benign
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000073184.12
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
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Likely benign
(Mar 18, 2019)
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criteria provided, single submitter
Method: clinical testing
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BRCA2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004741633.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(Aug 17, 2020)
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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: SCV000279246.7
First in ClinVar: May 29, 2016 Last updated: Apr 09, 2018 |
Comment:
This variant is associated with the following publications: (PMID: 21990134, 26566278, 21741379, 17924331, 20104584, 20960228, 26689913, 16683254, 24323938, 25085752, 25348012, 23108138, 29036293, 32444794)
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Benign
(Nov 19, 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: SCV000213510.5
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA … (more)
This alteration is classified as benign based on a combination of the following: 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)
Number of individuals with the variant: 1
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Likely benign
(Aug 13, 2014)
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criteria provided, single submitter
Method: literature only
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Breast-ovarian cancer, familial 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220593.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Likely benign
(Feb 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: SCV002497658.12
First in ClinVar: Apr 11, 2022 Last updated: Apr 15, 2024 |
Comment:
BRCA2: BS1
Number of individuals with the variant: 3
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Uncertain significance
(Feb 20, 2004)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000147054.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 2
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Asian
Observation 3:
Number of individuals with the variant: 2
Ethnicity/Population group: Near Eastern
Observation 4:
Number of individuals with the variant: 1
Ethnicity/Population group: Near Eastern, Iraqi
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733295.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002036096.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592103.2 First in ClinVar: Mar 08, 2017 Last updated: Apr 13, 2021 |
Comment:
The BRCA2 p.Lys2411Thr variant was identified in 2 of 6116 proband chromosomes (frequency: 0.000327) from individuals or families with hereditary breast and ovarian cancer (Borg_2010, … (more)
The BRCA2 p.Lys2411Thr variant was identified in 2 of 6116 proband chromosomes (frequency: 0.000327) from individuals or families with hereditary breast and ovarian cancer (Borg_2010, Capanu_2011, Laitman_2011) and in 1 of 2796 control chromosomes (freq. 0.00036). The variant was also identified in the following databases: dbSNP (ID: rs80358950) as “With other allele”, ClinVar (as benign by Ambry Genetics and VKGL Data-share Consensus, as likely benign by Counsyl, GeneDx, Quest Diagnostics, Color Genomics, Integrated Genetics, and Invitae, and as uncertain significance by COGR), Clinvitae (4x), LOVD 3.0 (6x), UMD-LSDB (4x as uncertain significance), and ARUP Laboratories (as not pathogenic). The variant was not identified in Cosmic, MutDB, BIC Database, or Zhejiang Colon Cancer Database. The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 13 of 246082 chromosomes at a frequency of 0.000053 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 9 of 5480 chromosomes (freq: 0.001642), and European (Non-Finnish) in 4 of 111574 chromosomes (freq: 0.000036); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. One functional study demonstrated homology-directed repair activity of the variant at a level similar to nonpathogenic variants (Guidugli_2014), and four studies using a multifactorial likelihood-ratio model predict the p.Lys2411Thr variant to be neutral (Easton_2007, Guidugli_2013, Lindor_2012, Pruss_2014_25085752). The p.Lys2411 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
Number of individuals with the variant: 3
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957465.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
High-throughput functional evaluation of BRCA2 variants of unknown significance. | Ikegami M | Nature communications | 2020 | PMID: 32444794 |
Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. | Parsons MT | Human mutation | 2019 | PMID: 31131967 |
Rare germline variants in known melanoma susceptibility genes in familial melanoma. | Goldstein AM | Human molecular genetics | 2017 | PMID: 29036293 |
BRCA Mutation-Related and Claudin-Low Breast Cancer: Blood Relatives or Stepsisters. | Madaras L | Pathobiology : journal of immunopathology, molecular and cellular biology | 2016 | PMID: 26566278 |
Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations. | Martelotto LG | Genome biology | 2014 | PMID: 25348012 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Functional assays for analysis of variants of uncertain significance in BRCA2. | Guidugli L | Human mutation | 2014 | PMID: 24323938 |
A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. | Guidugli L | Cancer research | 2013 | PMID: 23108138 |
Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel. | Laitman Y | Breast cancer research and treatment | 2012 | PMID: 22399190 |
A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). | Lindor NM | Human mutation | 2012 | PMID: 21990134 |
A new assay for functional screening of BRCA2 linker region mutations identifies variants that alter chemoresistance to cisplatin. | Warren CR | Experimental cell research | 2011 | PMID: 21741379 |
Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling. | Capanu M | Genetic epidemiology | 2011 | PMID: 21520273 |
Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. | Laitman Y | Breast cancer research and treatment | 2011 | PMID: 20960228 |
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. | Borg A | Human mutation | 2010 | PMID: 20104584 |
A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. | Easton DF | American journal of human genetics | 2007 | PMID: 17924331 |
A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting. | van der Hout AH | Human mutation | 2006 | PMID: 16683254 |
The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
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Text-mined citations for rs80358950 ...
HelpRecord last updated Apr 15, 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.