ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.229A>G (p.Thr77Ala)
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.229A>G (p.Thr77Ala)
Variation ID: 37780 Accession: VCV000037780.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32319238 (GRCh38) [ NCBI UCSC ] 13: 32893375 (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 May 1, 2024 Dec 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.229A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Thr77Ala missense NC_000013.11:g.32319238A>G NC_000013.10:g.32893375A>G NG_012772.3:g.8759A>G NG_017006.2:g.1126T>C LRG_293:g.8759A>G LRG_293t1:c.229A>G LRG_293p1:p.Thr77Ala U43746.1:n.457A>G - Protein change
- T77A
- Other names
- 457A>G
- Canonical SPDI
- NC_000013.11:32319237:A: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00004
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
Help
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
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
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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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Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Oct 6, 2023 | RCV000031361.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 31, 2023 | RCV000221509.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2021 | RCV000416556.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 8, 2023 | RCV000508014.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 14, 2023 | RCV001318869.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 29, 2023 | RCV003473163.1 |
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
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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
(Jan 28, 2021)
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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: SCV000600506.3
First in ClinVar: Sep 30, 2017 Last updated: Jan 03, 2022 |
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Uncertain significance
(Dec 14, 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: SCV001509588.4
First in ClinVar: Mar 14, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 77 of the BRCA2 protein (p.Thr77Ala). … (more)
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 77 of the BRCA2 protein (p.Thr77Ala). This variant is present in population databases (rs80358500, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer or head and neck carcinoma (PMID: 18284688, 29684080, 34598035). ClinVar contains an entry for this variant (Variation ID: 37780). 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%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 24448238, 24835992). 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
(May 28, 2019)
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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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Mendelics
Accession: SCV001138948.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Apr 27, 2021)
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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: SCV000494429.4
First in ClinVar: Feb 05, 2017 Last updated: May 21, 2021 |
Comment:
Variant summary: BRCA2 c.229A>G (p.Thr77Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: BRCA2 c.229A>G (p.Thr77Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251384 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.229A>G has been reported in the literature in individuals affected with Breast And Ovarian Cancer Syndrome (Lee_2008, Manie_2016, Sandoval_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported in the BIC database (Study ID 40821-presumably a whole gene deletion reported as BRCA1 943ins10, Stop275) and at our laboratory (BRCA1 c.5251C>T, p.Arg1751X), providing supporting evidence for a benign role. At least two publications provide experimental evidence evaluating an impact on protein function and report that this variant abolishes the Plk1 mediated phosphorylation of BRCA2 at residue Thr77, resulting in failure of BRCA2 localization to the Flemming body and incomplete cytokinesis, suggesting that this mutation may underlie the development of breast cancer (Yata_2014, Takaoka_2014). However, the implications of these observations on the established mechanisms of carcinogenesis are not clearly established. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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
(Aug 08, 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: SCV000566296.6
First in ClinVar: Apr 29, 2017 Last updated: Aug 18, 2023 |
Comment:
Observed in individuals with breast cancer (Lee et al., 2008; Yehia et al., 2018; Sandoval et al., 2021); Published functional studies are inconclusive: impaired interaction … (more)
Observed in individuals with breast cancer (Lee et al., 2008; Yehia et al., 2018; Sandoval et al., 2021); Published functional studies are inconclusive: impaired interaction of BRCA2 with PLK1 (Takaoka et al., 2014; Yata et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 457A>G; This variant is associated with the following publications: (PMID: 24448238, 24835992, 26920070, 26566862, 14647413, 29884841, 32377563, 18284688, 33606809, 31853058, 34598035, 29684080) (less)
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Uncertain significance
(Oct 29, 2023)
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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: SCV004211795.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Jan 22, 2018)
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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: SCV000785960.2
First in ClinVar: Sep 27, 2014 Last updated: Sep 27, 2014 |
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Uncertain Significance
(Oct 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004846747.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces threonine with alanine at codon 77 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with alanine at codon 77 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). Functional studies have shown that this variant disrupts BRCA2-PLK1 interaction. This variant has been reported in 2 individuals affected with breast cancer (PMID: 18284688, 33606809). This variant has been identified in 3/251384 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)
Number of individuals with the variant: 1
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Uncertain significance
(Mar 31, 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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Ambry Genetics
Accession: SCV000275166.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.T77A variant (also known as c.229A>G), located in coding exon 2 of the BRCA2 gene, results from an A to G substitution at nucleotide … (more)
The p.T77A variant (also known as c.229A>G), located in coding exon 2 of the BRCA2 gene, results from an A to G substitution at nucleotide position 229. The threonine at codon 77 is replaced by alanine, an amino acid with similar properties. This alteration was identified in a population-based study of early-onset breast cancer diagnoses (Lee E et al. Breast Cancer Res, 2008 Feb;10:R19). This alteration was also detected in a cohort of unrelated Brazilian individuals with breast cancer (Sandoval RL et al. PLoS One, 2021 Mar;16:e0247363). Functional studies indicate that the p.T77A alteration reduces BRCA2-PLK1 binding, which may impair BRCA2 localization and RAD51 recruitment (Takaoka M et al. Cancer Res. 2014 Mar;74(5):1518-28; Yata K et al. Cell Rep. 2014 Jun;7(5):1547-59). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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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: SCV000146412.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 4
Ethnicity/Population group: African
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Uncertain significance
(Apr 12, 2012)
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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: SCV000053966.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
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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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Germline variants in DNA repair genes are associated with young-onset head and neck cancer. | Cury SS | Oral oncology | 2021 | PMID: 34598035 |
Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis. | Sandoval RL | PloS one | 2021 | PMID: 33606809 |
Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. | Hart SN | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29884841 |
Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. | Yehia L | PLoS genetics | 2018 | PMID: 29684080 |
Genomic hallmarks of homologous recombination deficiency in invasive breast carcinomas. | Manié E | International journal of cancer | 2016 | PMID: 26317927 |
Molding BRCA2 function through its interacting partners. | Martinez JS | Cell cycle (Georgetown, Tex.) | 2015 | PMID: 26566862 |
BRCA2 coordinates the activities of cell-cycle kinases to promote genome stability. | Yata K | Cell reports | 2014 | PMID: 24835992 |
BRCA2 phosphorylated by PLK1 moves to the midbody to regulate cytokinesis mediated by nonmuscle myosin IIC. | Takaoka M | Cancer research | 2014 | PMID: 24448238 |
Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients. | Lee E | Breast cancer research : BCR | 2008 | PMID: 18284688 |
Phosphorylation of BRCA2 by the Polo-like kinase Plk1 is regulated by DNA damage and mitotic progression. | Lee M | Oncogene | 2004 | PMID: 14647413 |
Text-mined citations for rs80358500 ...
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.