VCV000052749.20 - ClinVar

NM_000059.4(BRCA2):c.9100C>T (p.Gln3034Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

9 submissions

9 submitters

5 conditions

Reviewed by expert panel

Pathogenic

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.9100C>T (p.Gln3034Ter)

Variation ID: 52749 Accession: VCV000052749.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32379896 (GRCh38) [ NCBI UCSC ] 13: 32954033 (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	Apr 1, 2014	May 1, 2024	Sep 8, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.9100C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Gln3034Ter	nonsense
NC_000013.11:g.32379896C>T
NC_000013.10:g.32954033C>T
NG_012772.3:g.69417C>T
LRG_293:g.69417C>T
LRG_293t1:c.9100C>T	LRG_293p1:p.Gln3034Ter
U43746.1:n.9328C>T

... more HGVS ... less HGVS

Protein change

Q3034*

Other names

Canonical SPDI

NC_000013.11:32379895:C:T

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

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.

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

Links

ClinGen: CA025978 dbSNP: rs80359163 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	18969	19128

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.
Breast-ovarian cancer, familial, susceptibility to, 2	Pathogenic (4)	reviewed by expert panel	Sep 8, 2016	RCV000114047.14
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 30, 2022	RCV000220911.12
Hereditary breast ovarian cancer syndrome	Pathogenic (2)	criteria provided, single submitter	Aug 10, 2023	RCV000496303.16
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 27, 2022	RCV002371870.9
Familial cancer of breast	Pathogenic (1)	criteria provided, single submitter	Aug 11, 2022	RCV003473428.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 08, 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: SCV000301353.2 First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016	Comment: Variant allele predicted to encode a truncated non-functional protein.
Pathogenic (Aug 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004210517.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Aug 10, 2023)	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: SCV001579242.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 28724667‚ 29446198‚ 29752822‚ 20104584 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 52749). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 28724667, 29446198, 29752822). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln3034*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). (less)
Pathogenic (Jan 27, 2022)	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: SCV002684187.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 28724667‚ 29093764‚ 29446198‚ 29752822‚ 29805665‚ 29922827 Comment: The p.Q3034* pathogenic mutation (also known as c.9100C>T), located in coding exon 22 of the BRCA2 gene, results from a C to T substitution at … (more) The p.Q3034* pathogenic mutation (also known as c.9100C>T), located in coding exon 22 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9100. This changes the amino acid from a glutamine to a stop codon within coding exon 22. This alteration has been identified in individuals diagnosed with breast and pancreatic cancer (Jian W et al. Hered Cancer Clin Pract, 2017 Oct;15:19; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Hu C et al. JAMA, 2018 06;319:2401-2409; Wei H et al. Oncol Lett, 2018 Jun;15:9420-9428; Li JY et al. Int J Cancer, 2019 01;144:281-289). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Molecular Endocrinology Laboratory, Christian Medical College Accession: SCV002003993.1 First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021	Publications: PubMed (1) PubMed: 20104584
Pathogenic (Oct 02, 2015)	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge Accession: SCV000328049.4 First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022
Pathogenic (Sep 30, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000278885.13 First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Jian 2017, Sun 2017, Rebbeck 2018, Li 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (gnomAD); Also known as 9328C>T; This variant is associated with the following publications: (PMID: 29446198, 22632462, 28724667, 29093764, 29752822, 31825140, 30702160, 29922827) (less)
Pathogenic (Dec 23, 2003)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000147536.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Number of individuals with the variant: 1
Pathogenic (Jan 31, 2014)	no assertion criteria provided Method: research	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000587987.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 52749). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 28724667, 29446198, 29752822). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln3034*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584).

Comment:

The p.Q3034* pathogenic mutation (also known as c.9100C>T), located in coding exon 22 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9100. This changes the amino acid from a glutamine to a stop codon within coding exon 22. This alteration has been identified in individuals diagnosed with breast and pancreatic cancer (Jian W et al. Hered Cancer Clin Pract, 2017 Oct;15:19; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Hu C et al. JAMA, 2018 06;319:2401-2409; Wei H et al. Oncol Lett, 2018 Jun;15:9420-9428; Li JY et al. Int J Cancer, 2019 01;144:281-289). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Jian 2017, Sun 2017, Rebbeck 2018, Li 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (gnomAD); Also known as 9328C>T; This variant is associated with the following publications: (PMID: 29446198, 22632462, 28724667, 29093764, 29752822, 31825140, 30702160, 29922827)

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer.	Li JY	International journal of cancer	2019	PMID: 29752822
Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.	Hu C	JAMA	2018	PMID: 29922827
Multicenter cross-sectional screening of the BRCA gene for Chinese high hereditary risk breast cancer populations.	Wei H	Oncology letters	2018	PMID: 29805665
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.	Rebbeck TR	Human mutation	2018	PMID: 29446198
Clinical and genetic characterization of hereditary breast cancer in a Chinese population.	Jian W	Hereditary cancer in clinical practice	2017	PMID: 29093764
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.	Sun J	Clinical cancer research : an official journal of the American Association for Cancer Research	2017	PMID: 28724667
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.	Borg A	Human mutation	2010	PMID: 20104584

Text-mined citations for rs80359163 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.9100C>T (p.Gln3034Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80359163 ...