ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.631+2T>G
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.631+2T>G
Variation ID: 9349 Accession: VCV000009349.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32326615 (GRCh38) [ NCBI UCSC ] 13: 32900752 (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 Feb 14, 2024 Jun 18, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.631+2T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001406719.1:c.631+2T>G splice donor NM_001406720.1:c.631+2T>G splice donor NM_001406721.1:c.631+2T>G splice donor NM_001406722.1:c.262+2T>G splice donor NC_000013.11:g.32326615T>G NC_000013.10:g.32900752T>G NG_012772.3:g.16136T>G LRG_293:g.16136T>G LRG_293t1:c.631+2T>G U43746.1:n.859+2T>G - Protein change
- Other names
- IVS7DS, T-G, +2
- IVS7+2T>G
- Canonical SPDI
- NC_000013.11:32326614:T:G
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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.
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
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. |
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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18542 | 18699 |
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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Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2007 | RCV000009943.14 | |
Pathogenic (7) |
reviewed by expert panel
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Jun 18, 2019 | RCV000031615.22 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 20, 2023 | RCV000044897.28 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 23, 2023 | RCV000129071.20 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000195357.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 19, 2017 | RCV000769680.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 20, 2018 | RCV000826135.12 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001353557.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 9, 2022 | RCV003147279.8 |
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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Pathogenic
(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: SCV001161558.2
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 5 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 5 based on posterior probability = 0.998311 (less)
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Pathogenic
(Jul 05, 2016)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694958.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The BRCA2 c.631+2T>G variant involves the alteration of a conserved intronic nucleotide located at the invariable splice acceptor site in intron 7 of … (more)
Variant summary: The BRCA2 c.631+2T>G variant involves the alteration of a conserved intronic nucleotide located at the invariable splice acceptor site in intron 7 of BRCA2. One in silico tool predicts a damaging outcome for this variant along with 5/5 splice site tools predicting the variant to result in the elimination of the splice donor site in intron 7. These predictions were confirmed by Pyne_J Hum Genet_2000 demonstrating that an RNA splicing product that deletes exon 7 was produced by the chromosome that carries the variant of interest. The deletion of exon 7 from the RNA alters the open reading frame by removing residues 249287 and incorporating 18 abnormal amino acids before terminating with an opal stop codon. This variant is absent in 121164 control chromosomes while it was reported in several HBOC spectrum patients. Furthermore, multiple clinical diagnostic laboratories and reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic. (less)
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Pathogenic
(Sep 19, 2017)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000901093.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019 |
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Pathogenic
(Feb 20, 2018)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967655.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The c.631+2T>G variant in BRCA2 has been identified in the homozygous or compoun d heterozygous state in 5 individuals with Fanconi anemia (Myer 2005, Myers … (more)
The c.631+2T>G variant in BRCA2 has been identified in the homozygous or compoun d heterozygous state in 5 individuals with Fanconi anemia (Myer 2005, Myers 2012 , Wagner 2004), and segregated with disease in 2 individuals from 2 families. It was absent from large population studies. The c.631+2T>G variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and has been shown t o cause altered splicing leading to an absent protein (Pyne 2000, Meyer 2005, Bi swas 2011). In summary, this variant meets criteria to be classified as pathogen ic for Fanconi anemia in an autosomal recessive manner. ACMG/AMP criteria applie d: PVS1, PM3_VeryStrong, PS4_Moderate, PM2, PP1. (less)
Number of individuals with the variant: 2
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Pathogenic
(Feb 20, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967740.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The c.631+2T>G variant in BRCA2 has been reported in >15 individuals with BRCA2- associated cancers (Pyne 2000, Wong-Brown 2015, Breast Cancer Information Core ( BIC) … (more)
The c.631+2T>G variant in BRCA2 has been reported in >15 individuals with BRCA2- associated cancers (Pyne 2000, Wong-Brown 2015, Breast Cancer Information Core ( BIC) database). It was absent from large population studies. The c.631+2T>G vari ant occurs in the invariant region (+/- 1,2) of the splice consensus sequence an d has been shown to cause altered splicing leading to an absent protein (Pyne 20 00, Meyer 2005, Biswas 2011). Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC) . In summary, this variant meets criteria to be classified as pathogenic for her editary breast and ovarian cancer syndrome in an autosomal dominant manner. ACMG /AMP criteria applied: PS4, PM2, PVS1. (less)
Number of individuals with the variant: 2
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Pathogenic
(Oct 02, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000327385.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000488785.2
First in ClinVar: Nov 05, 2016 Last updated: Dec 24, 2022 |
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Pathogenic
(Mar 22, 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: SCV000210249.10
First in ClinVar: Feb 24, 2015 Last updated: Apr 01, 2023 |
Comment:
Observed in the heterozygous state in individuals with a personal or family history of breast, ovarian, or other cancers (Evans et al., 2003; Wong-Brown et … (more)
Observed in the heterozygous state in individuals with a personal or family history of breast, ovarian, or other cancers (Evans et al., 2003; Wong-Brown et al., 2015; Ellingson et al., 2015; Maxwell et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as 859+2T>G; This variant is associated with the following publications: (PMID: 20455026, 26659639, 15070707, 25525159, 21548014, 25682074, 16115142, 26834852, 26296701, 24259538, 26920070, 25085752, 28831036, 29753700, 11185744, 16825431, 15645491, 30787465, 21719596, 32398771, 20927582, 33087929, 32719484, 12960223, 31131967) (less)
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Pathogenic
(May 23, 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: SCV000183773.8
First in ClinVar: Aug 06, 2014 Last updated: Apr 15, 2023 |
Comment:
The c.631+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 6 in the BRCA2 gene. This mutation has … (more)
The c.631+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 6 in the BRCA2 gene. This mutation has been reported in multiple families with hereditary breast and ovarian cancer (HBOC) syndrome (Pyne MT et al. J. Hum. Genet. 2000;45:351-7; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80). It has also been reported in the homozygous state and in the compound heterozygous state with other deleterious BRCA2 mutations in individuals who were either clinically diagnosed with or had symptoms of Fanconi anemia (Wagner JE et al. Blood. 2004 Apr;103:3226-9; Alter, BP et al. J. Med. Genet. 2007 Jan;44(1):1-9; Myers, K et al. Pediatr Blood Cancer 2012 Mar;58(3):462-5). This alteration results in substantial aberrant splicing in the set of samples tested (Ambry internal data). However, this alteration was able to fully complement the growth defect in Brca2-null mouse embryonic stem cells and surviving cells harboring this alteration retained substantial amounts of homology-directed DNA repair function (Mesman RLS et al. Genet Med, 2020 08;22:1355-1365). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. (less)
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Pathogenic
(Jun 05, 2019)
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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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Revvity Omics, Revvity
Accession: SCV002020255.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(May 23, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000683770.3
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant causes a T to G nucleotide substitution at the +2 position of intron 7 of the BRCA2 gene. An RNA study has detected … (more)
This variant causes a T to G nucleotide substitution at the +2 position of intron 7 of the BRCA2 gene. An RNA study has detected the out-of-frame skipping of exon 7 in carrier RNA (PMID: 11185744). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least ten individuals affected with breast and ovarian cancer (PMID: 11185744, 19620486, 20927582, 25682074, 28831036, 33471991; Leiden Open Variation Database DB-ID BRCA2_000039) and is reported to have segregation likelihood ratio for pathogenicity of 22.5147 (PMID: 31131967). This variant also has been reported in four homozygous and heterozygous carriers from three unrelated families who were affected with the recessive disease, Fanconi anemia (PMID: 15070707, 15645491, 21548014). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Apr 21, 2016)
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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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Michigan Medical Genetics Laboratories, University of Michigan
Accession: SCV000267734.1
First in ClinVar: Sep 27, 2014 Last updated: Sep 27, 2014 |
Tissue: Blood
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Pathogenic
(Jan 22, 2019)
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criteria provided, single submitter
Method: research
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI_GT
Accession: SCV000778601.2 First in ClinVar: Sep 28, 2017 Last updated: Sep 24, 2019 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
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Pathogenic
(May 06, 2021)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001471730.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 08, 2022 |
Comment:
The BRCA2 c.631+2T>G variant (rs81002899), also known as IVS7+2T>G, is reported in the literature in multiple individuals with a personal or family history of breast … (more)
The BRCA2 c.631+2T>G variant (rs81002899), also known as IVS7+2T>G, is reported in the literature in multiple individuals with a personal or family history of breast and/or ovarian cancer (Pyne 2000, Wagner 2004). In addition, this variant has been described in the homozygous state or in trans to another pathogenic BRCA2 variant in individuals affected with Fanconi anemia (Meyer 2005, Wagner 2004). The c.631+2T>G variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice donor site of intron 7, which is likely to disrupt gene function. Indeed, functional assays suggest this variant causes skipping of exon 7, resulting in mRNA degradation and a lack of detectable protein (Pyne 2000, Meyer 2005). Based on available information, this variant is considered to be pathogenic. References: Meyer S et al. A cross-linker-sensitive myeloid leukemia cell line from a 2-year-old boy with severe Fanconi anemia and biallelic FANCD1/BRCA2 mutations. Genes Chromosomes Cancer. 2005 Apr;42(4):404-15. Pyne MT et al. The BRCA2 genetic variant IVS7 + 2T-->G is a mutation. J Hum Genet. 2000;45(6):351-7. Wagner JE et al. Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia. Blood. 2004 Apr 15;103(8):3226-9. (less)
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Pathogenic
(Dec 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003836035.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Jun 20, 2023)
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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: SCV000296701.6
First in ClinVar: Sep 27, 2014 Last updated: Jan 06, 2024 |
Comment:
The BRCA2 c.631+2T>G variant is located in a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. This variant has been reported in the … (more)
The BRCA2 c.631+2T>G variant is located in a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2), 31090900 (2019), 29625052 (2018), 26689913 (2015), 25682074 (2015), 26296701 (2015), 11185744 (2000)). Additionally, the variant is reported to be damaging to BRCA2 function by causing the premature truncation of exon 7 (PMIDs: PMIDs: 31131967 (2019), 21719596 (2011), 11185744 (2000)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Jan 31, 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: SCV000072910.14
First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 7 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 7 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with BRCA2-related conditions (PMID: 11185744, 15070707, 15645491, 16825431, 21719596, 25682074, 26296701). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS7+2T>G. ClinVar contains an entry for this variant (Variation ID: 9349). Studies have shown that disruption of this splice site results in skipping of exon 7 and introduces a premature termination codon (PMID: 11185744, 21719596; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 29, 2002)
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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: SCV000147336.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 9
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Native American, Central/Eastern European
Observation 3:
Number of individuals with the variant: 7
Ethnicity/Population group: Western European
Observation 4:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Norwegian German
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Pathogenic
(Jan 08, 2013)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: not provided
Allele origin:
germline
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Sharing Clinical Reports Project (SCRP)
Accession: SCV000054222.6
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
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Pathogenic
(Jan 01, 2007)
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no assertion criteria provided
Method: literature only
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FANCONI ANEMIA, COMPLEMENTATION GROUP D1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030164.4
First in ClinVar: Apr 04, 2013 Last updated: May 21, 2018 |
Comment on evidence:
In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Wagner et al. (2004) found a splice site mutation in intron 7 of the … (more)
In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Wagner et al. (2004) found a splice site mutation in intron 7 of the BRCA2 gene, IVS7+2T-G, in compound heterozygosity with a 4-bp deletion. One of the brothers developed acute myeloblastic leukemia and the other Wilms tumor, both before 1 year of age. An unrelated patient identified by Meyer et al. (2005) also carried this mutation; he developed acute myeloblastic leukemia as well. Alter et al. (2007) included these patients in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. (less)
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Pathogenic
(Jan 31, 2014)
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no assertion criteria provided
Method: research
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587557.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
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: SCV000591703.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The c.631+2T>G variant was identified in the literature associated with Fanconi Anaemia in a compound heterozygous state and with breast cancer in a heterozygous state … (more)
The c.631+2T>G variant was identified in the literature associated with Fanconi Anaemia in a compound heterozygous state and with breast cancer in a heterozygous state (Pyne 2000, Biswas 2011). The variant was identified in dbSNP (ID: rs81002899) with ‚ÄúPathogenic/untested allele,‚Äù and was not found in NHLBI Exome Sequencing Project (Exome Variant Server) or Exome Aggregation Consortium (ExAC) databases. The variant was also identified in the ClinVar database 6X and classified as a pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports, Invitae, Ambry Genetics, GeneDx, BIC and OMIM. The c.631+2T>G variant was identified in the BIC database 18X with clinical importance and in ARUP Laboratories 1X classified as ‚Äúdefinitely pathogenic‚Äù, The Fanconi Anaemia (FA) LOVD database identified the variant 3X classified as ‚Äúpredicted deleterious‚Äù. The c.631+2T>G variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. Biochemical and genetic analysis demonstrates an RNA splicing product that deletes exon 7 was produced by the chromosome that carries BRCA2 c.631+2T>G. The deletion of exon 7 from the RNA alters the open reading frame by removing residues 249‚Äì287 and incorporating 18 abnormal amino acids before stop codon terminating, this is strong evidence that this variant is deleterious (Pyne 2000). In addition studies of functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell‚Äìbased assay, the c.631+2T>G allele produces an alternatively spliced transcript lacking exons 4-7, encoding an in-frame BRCA2 protein with an internal deletion of 105 amino acids (BRCA2‚à Ü105). Evaluation of this transcript in normal and leukemia cells suggests that BRCA2‚à Ü105 is proficient in homologous recombination-mediated DNA repair as measured by different functional assays. The authors concluded that the BRCA2‚à Ü105 transcript may lead to a milder FA phenotype, however further evidence would be required to confirm this finding (Biswas 2011). In summary, based on the above information, this variant meets our laboratory‚Äôs criteria to be classified as pathogenic. (less)
Number of individuals with the variant: 2
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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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The germline mutational landscape of genitourinary cancers and its indication for prognosis and risk. | Yang Y | BMC urology | 2022 | PMID: 36451132 |
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 |
Exome sequencing and characterization of 49,960 individuals in the UK Biobank. | Van Hout CV | Nature | 2020 | PMID: 33087929 |
Population genetic screening efficiently identifies carriers of autosomal dominant diseases. | Grzymski JJ | Nature medicine | 2020 | PMID: 32719484 |
Alternative mRNA splicing can attenuate the pathogenicity of presumed loss-of-function variants in BRCA2. | Mesman RLS | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32398771 |
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 |
Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers. | Nones K | Annals of oncology : official journal of the European Society for Medical Oncology | 2019 | PMID: 31090900 |
Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. | Waszak SM | The Lancet. Oncology | 2018 | PMID: 29753700 |
Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers. | Maxwell KN | Nature communications | 2017 | PMID: 28831036 |
BRCA2 minor transcript lacking exons 4-7 supports viability in mice and may account for survival of humans with a pathogenic biallelic mutation. | Thirthagiri E | Human molecular genetics | 2016 | PMID: 26920070 |
Fanconi anemia-D1 due to homozygosity for the BRCA2 gene Cypriot founder mutation: A case report. | Loizidou MA | Oncology letters | 2016 | PMID: 26834852 |
Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
Exome sequencing reveals frequent deleterious germline variants in cancer susceptibility genes in women with invasive breast cancer undergoing neoadjuvant chemotherapy. | Ellingson MS | Breast cancer research and treatment | 2015 | PMID: 26296701 |
Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer. | Wong-Brown MW | Breast cancer research and treatment | 2015 | PMID: 25682074 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
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 |
Evaluation of a 5-tier scheme proposed for classification of sequence variants using bioinformatic and splicing assay data: inter-reviewer variability and promotion of minimum reporting guidelines. | Walker LC | Human mutation | 2013 | PMID: 23893897 |
Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ. | Bayraktar S | Cancer | 2012 | PMID: 22009639 |
The clinical phenotype of children with Fanconi anemia caused by biallelic FANCD1/BRCA2 mutations. | Myers K | Pediatric blood & cancer | 2012 | PMID: 21548014 |
A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. | Biswas K | Blood | 2011 | PMID: 21719596 |
Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. | Ding YC | Breast cancer research and treatment | 2011 | PMID: 20927582 |
Detecting BRCA2 protein truncation in tissue biopsies to identify breast cancers that arise in BRCA2 gene mutation carriers. | Watson P | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2009 | PMID: 19620486 |
Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. | Alter BP | Journal of medical genetics | 2007 | PMID: 16825431 |
A cross-linker-sensitive myeloid leukemia cell line from a 2-year-old boy with severe Fanconi anemia and biallelic FANCD1/BRCA2 mutations. | Meyer S | Genes, chromosomes & cancer | 2005 | PMID: 15645491 |
Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia. | Wagner JE | Blood | 2004 | PMID: 15070707 |
Sensitivity of BRCA1/2 mutation testing in 466 breast/ovarian cancer families. | Evans DG | Journal of medical genetics | 2003 | PMID: 12960223 |
The BRCA2 genetic variant IVS7 + 2T-->G is a mutation. | Pyne MT | Journal of human genetics | 2000 | PMID: 11185744 |
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 rs81002899 ...
HelpRecord last updated Apr 20, 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.