ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.5961G>T (p.Gln1987His)
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(6); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.5961G>T (p.Gln1987His)
Variation ID: 55935 Accession: VCV000055935.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32340316 (GRCh38) [ NCBI UCSC ] 13: 32914453 (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 Jul 24, 2013 May 1, 2024 Dec 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.5961G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Gln1987His missense NC_000013.11:g.32340316G>T NC_000013.10:g.32914453G>T NG_012772.3:g.29837G>T LRG_293:g.29837G>T LRG_293t1:c.5961G>T LRG_293p1:p.Gln1987His - Protein change
- Q1987H
- Other names
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- Canonical SPDI
- NC_000013.11:32340315:G:T
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
18724 | 18882 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Likely pathogenic (1) |
no assertion criteria provided
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- | RCV000049344.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 25, 2020 | RCV000480427.3 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 23, 2023 | RCV000561617.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 18, 2023 | RCV000637728.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 6, 2018 | RCV000779990.1 |
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
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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
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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
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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
(Apr 20, 2018)
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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: SCV000566687.4
First in ClinVar: Apr 29, 2017 Last updated: Apr 17, 2019 |
Comment:
This variant is denoted BRCA2 c.5961G>T at the cDNA level, p.Gln1987His (Q1987H) at the protein level, and results in the change of a Glutamine to … (more)
This variant is denoted BRCA2 c.5961G>T at the cDNA level, p.Gln1987His (Q1987H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAT). Using alternate nomenclature, this variant would be defined as BRCA2 6189G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gln1987His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Gln1987His occurs at a position that is not conserved and is located in the BRC repeat region and RAD51 binding domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Gln1987His is pathogenic or benign. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Jul 06, 2018)
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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: SCV000916972.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: BRCA2 c.5961G>T (p.Gln1987His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign … (more)
Variant summary: BRCA2 c.5961G>T (p.Gln1987His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 120618 control chromosomes (ExAC). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5961G>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Feb 25, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469693.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Uncertain significance
(Jun 09, 2021)
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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: SCV001734886.2
First in ClinVar: Mar 25, 2020 Last updated: Jan 08, 2022 |
Comment:
This missense variant replaces glutamine with histidine at codon 1987 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glutamine with histidine at codon 1987 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/250656 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Mar 23, 2023)
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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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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV003850816.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Comment:
BRCA2 exon 11 coldspot. Reclassification based on statistical prior probability.
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Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
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Uncertain significance
(Dec 18, 2023)
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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: SCV000759201.7
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1987 of the BRCA2 protein (p.Gln1987His). … (more)
This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1987 of the BRCA2 protein (p.Gln1987His). This variant is present in population databases (rs387907575, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 55935). 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 BRCA2 protein function with a negative predictive value of 95%. 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
(Jun 17, 2022)
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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: SCV000661251.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.Q1987H variant (also known as c.5961G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide … (more)
The p.Q1987H variant (also known as c.5961G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 5961. The glutamine at codon 1987 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not 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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probable-pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Breast-ovarian cancer, familial 2
Affected status: not provided
Allele origin:
germline
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Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences
Accession: SCV000081776.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013
Comment:
This SNP was detected by DHPLC and Direct DNA Sequencing. The SNP was observed (in its heterozygous form) only in patients with breast cancer but … (more)
This SNP was detected by DHPLC and Direct DNA Sequencing. The SNP was observed (in its heterozygous form) only in patients with breast cancer but not healthy control group. The study contributors are : Safoora Deihimi, Abbas Ghaderi, Abdolrasoul Talei, Nasrollah Erfani. (less)
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Comment:
Converted during submission to Likely pathogenic.
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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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Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". | Dines JN | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31911673 |
Text-mined citations for rs387907575 ...
HelpRecord last updated May 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.