NM_032043.3(BRIP1):c.3240dup (p.Ala1081fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Nov 20, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000579524.13

Allele description [Variation Report for NM_032043.3(BRIP1):c.3240dup (p.Ala1081fs)]

NM_032043.3(BRIP1):c.3240dup (p.Ala1081fs)

Gene:

BRIP1:BRCA1 interacting DNA helicase 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

17q23.2

Genomic location:

Preferred name:

NM_032043.3(BRIP1):c.3240dup (p.Ala1081fs)

HGVS:

NC_000017.11:g.61683806dup
NG_007409.2:g.184754dup
NM_032043.3:c.3240dupMANE SELECT
NP_114432.2:p.Ala1081fs
NP_114432.2:p.Ala1081fs
LRG_300t1:c.3240dup
LRG_300:g.184754dup
LRG_300p1:p.Ala1081fs
NC_000017.10:g.59761166_59761167insA
NC_000017.10:g.59761167dup
NM_032043.2:c.3240dup
NM_032043.2:c.3240dupT

Protein change:

A1081fs

Links:

dbSNP: rs779741278

NCBI 1000 Genomes Browser:

rs779741278

Molecular consequence:

NM_032043.3:c.3240dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000684251	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 6, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20159562, 21127055, 22792074, 27498913, 31214711, 32566746, 25741868
SCV001180738	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20068231, 22792074, 32566746, 35986085 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000684251

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 6, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001180738

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Nov 20, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

BACH1/FANCJ acts with TopBP1 and participates early in DNA replication checkpoint control.

Gong Z, Kim JE, Leung CC, Glover JN, Chen J.

Mol Cell. 2010 Feb 12;37(3):438-46. doi: 10.1016/j.molcel.2010.01.002.

PubMed [citation]

PMID:: 20159562
PMCID:: PMC3695484

Molecular basis of BACH1/FANCJ recognition by TopBP1 in DNA replication checkpoint control.

Leung CC, Gong Z, Chen J, Glover JN.

J Biol Chem. 2011 Feb 11;286(6):4292-301. doi: 10.1074/jbc.M110.189555. Epub 2010 Dec 2.

PubMed [citation]

PMID:: 21127055
PMCID:: PMC3039391

See all PubMed Citations (9)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000684251.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant inserts 1 nucleotide in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. The truncated protein is expected to disrupt the TopBP1 binding domain (a.a. 1106-1178) and an acetylation site (p.Lys1249) in the C-terminus, which have been reported to play an important role in DNA replication-stress response and maintaining genomic stability (PMID: 20159562, 21127055, 22792074). This variant has been reported in individuals affected with sarcoma, prostate cancer, and bilateral breast cancer (PMID: 27498913, 31214711, 32566746). This variant has been identified in 1/251228 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 Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV001180738.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The c.3240dupT variant, located in coding exon 19 of the BRIP1 gene, results from a duplication of T at nucleotide position 3240, causing a translational frameshift with a predicted alternate stop codon (p.A1081Cfs*5). This stop codon occurs near the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and removes the last 165 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, structural and functional analysis suggest that at least two residues contained in this deleted region (Ser1237 and Lys1249) have functional importance (Olsen JV et al. Sci Signal. 2010 Jan;3:ra3; Xie J et al. PLoS Genet. 2012 Jul;8:e1002786). This alteration was detected in a patient diagnosed with bilateral breast cancer at age 47, her mother, who was diagnosed with breast cancer at age 70, and a maternal aunt, who was diagnosed with breast cancer at ages 58 and 70 (Kaneyasu T et al. NPJ Breast Cancer. 2020 Jun;6:25). This alteration has also been detected in a cohort of 549 Japanese men with prostate cancer (Kimura H et al. Br J Cancer, 2022 Nov;127:1680-1690). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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