VCV000141382.25 - ClinVar

NM_032043.3(BRIP1):c.1240C>T (p.Gln414Ter)

Germline

Classification

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.

(11)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_032043.3(BRIP1):c.1240C>T (p.Gln414Ter)

Variation ID: 141382 Accession: VCV000141382.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q23.2 17: 61799200 (GRCh38) [ NCBI UCSC ] 17: 59876561 (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	Jan 6, 2017	Sep 16, 2024	Dec 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_032043.3:c.1240C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_114432.2:p.Gln414Ter	nonsense
NC_000017.11:g.61799200G>A
NC_000017.10:g.59876561G>A
NG_007409.2:g.69360C>T
LRG_300:g.69360C>T
LRG_300t1:c.1240C>T	LRG_300p1:p.Gln414Ter

... more HGVS ... less HGVS

Protein change

Q414*

Other names

Canonical SPDI

NC_000017.11:61799199:G:A

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA165277 dbSNP: rs368796923 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.
BRIP1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	5625	5682

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	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 2, 2022	RCV000129878.12
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 27, 2023	RCV000445256.6
Fanconi anemia complementation group J	Likely pathogenic (1)	criteria provided, single submitter	Sep 13, 2016	RCV000409609.3
Familial cancer of breast Fanconi anemia complementation group J	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 6, 2023	RCV000701846.11
Ovarian neoplasm	Likely pathogenic (1)	criteria provided, single submitter	Sep 13, 2016	RCV000411128.3
BRIP1-associated familial cancer predisposition	Likely pathogenic (1)	criteria provided, single submitter	-	RCV003335116.1
Familial cancer of breast	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 30, 2023	RCV000781179.4

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 (Jun 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004217065.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Nov 01, 2021)	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: SCV000184695.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 27153395 Comment: The p.Q414* pathogenic mutation (also known as c.1240C>T), located in coding exon 8 of the BRIP1 gene, results from a C to T substitution at … (more) The p.Q414* pathogenic mutation (also known as c.1240C>T), located in coding exon 8 of the BRIP1 gene, results from a C to T substitution at nucleotide position 1240. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This variant has been identified in at least one patient with a personal and family history of breast and/or ovarian cancer (Maxwell KN et al. Am J Hum Genet. 2016 May;98:801-817). 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)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	BRIP1-associated familial cancer predisposition Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046096.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This nonsense variant found in exon 9 of 20 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated … (more) This nonsense variant found in exon 9 of 20 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has not been reported in affected individuals in the literature to our knowledge; however, loss-of-function variation in BRIP1 is an established mechanism of disease (PMID: 16116423, 17033622, 21964575). The c.1240C>T (p.Gln414Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/251108) and thus presumed to be rare. Based on the available evidence, the c.1240C>T (p.Gln414Ter) variant is classified as Likely Pathogenic. (less)
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Fanconi anemia complementation group J Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893464.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Likely pathogenic (Aug 03, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000919060.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (2) PubMed: 29922827‚ 28152038 Comment: Variant summary: BRIP1 c.1240C>T (p.Gln414X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: BRIP1 c.1240C>T (p.Gln414X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1871C>A (p.Ser624X), c.2255_2256delAA (p.Lys752fsX12), c.2392C>T (p.Arg798X)). The variant allele was found at a frequency of 4.1e-06 in 245868 control chromosomes (gnomAD). The variant, c.1240C>T, has been reported in the literature with limited information (Hu_2018, La Duca_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Likely pathogenic (Sep 13, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Fanconi anemia complementation group J Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000489993.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022
Likely pathogenic (Sep 13, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Ovarian cancer Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000489994.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022
Pathogenic (Mar 01, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004019415.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Pathogenic (Feb 02, 2022)	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: SCV000689256.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Comment: This variant changes 1 nucleotide in exon 9 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in … (more) This variant changes 1 nucleotide in exon 9 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251108 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Dec 06, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial cancer of breast Fanconi anemia complementation group J Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000830666.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 28492532‚ 16116423‚ 17033622‚ 21964575 Comment: This sequence change creates a premature translational stop signal (p.Gln414) in the BRIP1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Gln414) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is present in population databases (rs368796923, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141382). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 27, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000515873.7 First in ClinVar: Mar 08, 2017 Last updated: Sep 16, 2024	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 … (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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in at least one individual undergoing multi-gene panel testing in a clinical laboratory (PMID: 28152038); This variant is associated with the following publications: (PMID: 29922827, 28152038, 29368626) (less)
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Comment:

The p.Q414* pathogenic mutation (also known as c.1240C>T), located in coding exon 8 of the BRIP1 gene, results from a C to T substitution at nucleotide position 1240. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This variant has been identified in at least one patient with a personal and family history of breast and/or ovarian cancer (Maxwell KN et al. Am J Hum Genet. 2016 May;98:801-817). 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:

This nonsense variant found in exon 9 of 20 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has not been reported in affected individuals in the literature to our knowledge; however, loss-of-function variation in BRIP1 is an established mechanism of disease (PMID: 16116423, 17033622, 21964575). The c.1240C>T (p.Gln414Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/251108) and thus presumed to be rare. Based on the available evidence, the c.1240C>T (p.Gln414Ter) variant is classified as Likely Pathogenic.

Comment:

Variant summary: BRIP1 c.1240C>T (p.Gln414X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1871C>A (p.Ser624X), c.2255_2256delAA (p.Lys752fsX12), c.2392C>T (p.Arg798X)). The variant allele was found at a frequency of 4.1e-06 in 245868 control chromosomes (gnomAD). The variant, c.1240C>T, has been reported in the literature with limited information (Hu_2018, La Duca_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

This variant changes 1 nucleotide in exon 9 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251108 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Gln414*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is present in population databases (rs368796923, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141382). For these reasons, this variant has been classified as Pathogenic.

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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in at least one individual undergoing multi-gene panel testing in a clinical laboratory (PMID: 28152038); This variant is associated with the following publications: (PMID: 29922827, 28152038, 29368626)

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
Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.	Hu C	JAMA	2018	PMID: 29922827
Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels.	LaDuca H	PloS one	2017	PMID: 28152038
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
Mutations in BRIP1 confer high risk of ovarian cancer.	Rafnar T	Nature genetics	2011	PMID: 21964575
Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles.	Seal S	Nature genetics	2006	PMID: 17033622
The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J.	Levitus M	Nature genetics	2005	PMID: 16116423

Text-mined citations for rs368796923 ...

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_032043.3(BRIP1):c.1240C>T (p.Gln414Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs368796923 ...