VCV000051269.52 - ClinVar

NM_000059.4(BRCA2):c.231T>G (p.Thr77=)

Germline

Top reviewed classifications are shown here.

Submission summary:

24 submissions

24 submitters

9 conditions

Reviewed by expert panel

Benign

Sep 2016 by Evidence-based…

for Breast-ovarian cancer, familial, susceptibility to, 2

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.231T>G (p.Thr77=)

Variation ID: 51269 Accession: VCV000051269.52

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32319240 (GRCh38) [ NCBI UCSC ] 13: 32893377 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 9, 2014	May 1, 2024	Sep 28, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.231T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Thr77=	synonymous
NC_000013.11:g.32319240T>G
NC_000013.10:g.32893377T>G
NG_012772.3:g.8761T>G
NG_017006.2:g.1124A>C
LRG_293:g.8761T>G
LRG_293t1:c.231T>G	LRG_293p1:p.Thr77=

... more HGVS ... less HGVS

Protein change

Other names

NP_000050.3:p.Thr77=

Canonical SPDI

NC_000013.11:32319239:T:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Normal function

Global minor allele frequency (GMAF) Help The 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.

0.00300 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00047

Exome Aggregation Consortium (ExAC) 0.00068

The Genome Aggregation Database (gnomAD) 0.00191

Trans-Omics for Precision Medicine (TOPMed) 0.00206

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00231

1000 Genomes Project 0.00300

1000 Genomes Project 30x 0.00344

Links

ClinGen: CA014923 dbSNP: rs114446594 VarSome

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
Gene	OMIM	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.
BRCA2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	18962	19121

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.
Hereditary cancer-predisposing syndrome	Benign (3)	criteria provided, multiple submitters, no conflicts	Sep 29, 2020	RCV000129199.11
Breast-ovarian cancer, familial, susceptibility to, 2	Benign (5)	reviewed by expert panel	Sep 28, 2016	RCV000119247.11
Hereditary breast ovarian cancer syndrome	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000195302.21
not specified	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000176971.25
Familial cancer of breast	Benign (1)	criteria provided, single submitter	Feb 23, 2017	RCV000466597.5
not provided	Likely benign (2)	no assertion criteria provided	Aug 2, 2017	RCV000656582.12
Malignant tumor of breast	Benign (1)	no assertion criteria provided	-	RCV001353938.5
Breast-ovarian cancer, familial, susceptibility to, 2 Familial cancer of breast Fanconi anemia complementation group D1 Glioma susceptibility 3 Malignant tumor of prostate Medulloblastoma Pancreatic cancer, susceptibility to, 2 Wilms tumor 1	Benign (1)	criteria provided, single submitter	Mar 18, 2022	RCV002496687.4
Breast and/or ovarian cancer	Likely benign (1)	criteria provided, single submitter	Jun 6, 2023	RCV003149670.6

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.
Benign (Sep 28, 2016)	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2015)) Method: curation	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Accession: SCV000321190.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014	Comment: Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.0113 (African), derived from 1000 genomes (2013-05-02).
Benign (Feb 23, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast (Autosomal dominant inheritance) Affected status: no Allele origin: germline	Baylor Genetics Accession: SCV000541058.1 First in ClinVar: Apr 17, 2017 Last updated: Apr 17, 2017
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001138949.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020
Benign (Mar 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Medulloblastoma Familial prostate cancer Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002809037.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely benign (Jun 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV003838813.2 First in ClinVar: Mar 11, 2023 Last updated: Feb 04, 2024
Benign (Nov 19, 2014)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000183943.7 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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)
Benign (Apr 21, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Michigan Medical Genetics Laboratories, University of Michigan Accession: SCV000267726.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014	Tissue: Blood
Likely benign (Mar 28, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000538469.1 First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 5 B/LB; Silent (meets our criteria for LB) (less) Method: Genome/Exome Filtration
Benign (Nov 17, 2016)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602827.1 First in ClinVar: Aug 27, 2017 Last updated: Aug 27, 2017
Benign (Dec 08, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000805671.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018
Benign (Dec 29, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000228765.5 First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018	Publications: PubMed (2) PubMed: 12552570‚ 20683152 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2 http://exac.broadinstitute.org/g… http://exac.broadinstitute.org/gene/ENSG00000139618 http://www.ncbi.nlm.nih.gov/clin… http://www.ncbi.nlm.nih.gov/clinvar/?term=NM_000059.3%3Ac.231T%3EG http://www.ncbi.nlm.nih.gov/vari… http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/?chr=13&from=32893377&to=32893377 http://www.umd.be/BRCA2/ http://www.umd.be/BRCA2/ Number of individuals with the variant: 1 Sex: mixed
Benign (Sep 29, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002533307.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Likely benign (Nov 30, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Hereditary Breast and Ovarian Cancer Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000296852.3 First in ClinVar: Jan 31, 2016 Last updated: Dec 24, 2022
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000071986.13 First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024
Likely benign (Feb 14, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary breast and ovarian cancer syndrome(HBOC) Affected status: unknown Allele origin: germline	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV000576432.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017
Benign (Nov 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State Accession: SCV002025793.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: DOI: 10.3389/fgene.2022.834265 DOI: 10.3389/fgene.2022.834265 Number of individuals with the variant: 1 Geographic origin: South Africa Testing laboratory: National Health Laboratory Service (NHLS)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM) Accession: SCV002318936.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (2) PubMed: 20683152‚ 22684231 Age: 30-39 years Sex: female Geographic origin: Algeria
Benign (Mar 10, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000683478.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
Likely benign (Mar 14, 2014)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: literature only	Breast-ovarian cancer, familial 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000154083.2 First in ClinVar: Jun 09, 2014 Last updated: Dec 24, 2022	Publications: PubMed (4) PubMed: 22505045‚ 21673748‚ 12552570‚ 20683152
Likely benign (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002761132.3 First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001906238.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001972368.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Likely benign (Aug 02, 2017)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000778633.1 First in ClinVar: Jun 25, 2018 Last updated: Jun 25, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	Malignant tumor of breast Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000591665.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021	Comment: The p.Thr77Thr variant has been identified in 22 out of 1134 proband chromosomes (frequency 0.019) in individuals with breast and ovarian cancer phenotype, and was … (more) The p.Thr77Thr variant has been identified in 22 out of 1134 proband chromosomes (frequency 0.019) in individuals with breast and ovarian cancer phenotype, and was not identified in 300 control chromosomes (Cherbal 2010, Hadjisawas 2004, Hadjisawas 2003, Fackenthal 2011, Baumbach-abstract). However, it is listed in dbSNP database (ID#: rs114446594) with an average heterozygosity of 0.005+/-0.051, therefore increasing the likelihood of this variant to be benign. This variant is not expected to have clinical significance because it does not alter an amino acid residue, and is not located near a splice junction. In the UMD database, this variant has been identified in 3 (out of 10) individuals with breast or ovarian cancers, where a second pathogenic BRCA1 or BRCA2 mutation was also detected, suggesting that this is a benign variant. In a recent study, partial exon 3 skipping was suggested to be associated with this variant, however this information is not very predictive of pathogenicity (Thery 2011). In summary, based on above information we would lean towards a more benign role for this variant, therefore this variant is classified as Benign. (less)
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Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.

Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 5 B/LB; Silent (meets our criteria for LB)

Comment:

The p.Thr77Thr variant has been identified in 22 out of 1134 proband chromosomes (frequency 0.019) in individuals with breast and ovarian cancer phenotype, and was not identified in 300 control chromosomes (Cherbal 2010, Hadjisawas 2004, Hadjisawas 2003, Fackenthal 2011, Baumbach-abstract). However, it is listed in dbSNP database (ID#: rs114446594) with an average heterozygosity of 0.005+/-0.051, therefore increasing the likelihood of this variant to be benign. This variant is not expected to have clinical significance because it does not alter an amino acid residue, and is not located near a splice junction. In the UMD database, this variant has been identified in 3 (out of 10) individuals with breast or ovarian cancers, where a second pathogenic BRCA1 or BRCA2 mutation was also detected, suggesting that this is a benign variant. In a recent study, partial exon 3 skipping was suggested to be associated with this variant, however this information is not very predictive of pathogenicity (Thery 2011). In summary, based on above information we would lean towards a more benign role for this variant, therefore this variant is classified as Benign.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Normal function			University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM) Accession: SCV002318936.1	Publications PubMed (2)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Prevalence of Clinically Relevant Germline BRCA Variants in a Large Unselected South African Breast and Ovarian Cancer Cohort: A Public Sector Experience.	Van der Merwe NC	Frontiers in genetics	2022	DOI: 10.3389/fgene.2022.834265
BRCA1 and BRCA2 unclassified variants and missense polymorphisms in Algerian breast/ovarian cancer families.	Cherbal F	Disease markers	2012	PMID: 22684231
Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants.	Houdayer C	Human mutation	2012	PMID: 22505045
Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes.	Théry JC	European journal of human genetics : EJHG	2011	PMID: 21673748
BRCA1 and BRCA2 germline mutations screening in Algerian breast/ovarian cancer families.	Cherbal F	Disease markers	2010	PMID: 20683152
BRCA2 germline mutations in Cypriot patients with familial breast/ovarian cancer.	Hadjisavvas A	Human mutation	2003	PMID: 12552570
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2	-	-	-	-
http://www.umd.be/BRCA2/	-	-	-	-

Text-mined citations for rs114446594 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.231T>G (p.Thr77=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs114446594 ...