NM_032043.3(BRIP1):c.3187del (p.Ser1063fs) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 24, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003785608.2

Allele description [Variation Report for NM_032043.3(BRIP1):c.3187del (p.Ser1063fs)]

NM_032043.3(BRIP1):c.3187del (p.Ser1063fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

17q23.2

Genomic location:

Preferred name:

NM_032043.3(BRIP1):c.3187del (p.Ser1063fs)

HGVS:

NC_000017.11:g.61683859del
NG_007409.2:g.184701del
NM_032043.3:c.3187delMANE SELECT
NP_114432.2:p.Ser1063Argfs
NP_114432.2:p.Ser1063fs
LRG_300t1:c.3187del
LRG_300:g.184701del
LRG_300p1:p.Ser1063Argfs
NC_000017.10:g.59761220del
NM_032043.2:c.3187delT

Protein change:

S1063fs

Molecular consequence:

NM_032043.3:c.3187del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial; Hereditary breast cancer
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

Name:: Fanconi anemia complementation group J
Identifiers:: MONDO: MONDO:0012187; MedGen: C1836860; Orphanet: 84; OMIM: 609054

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Streptanthus insignis subsp. insignis voucher DAV:TuckerM 4d-069 18S ribosomal R...
Streptanthus insignis subsp. insignis voucher DAV:TuckerM 4d-069 18S ribosomal RNA gene, partial sequence; internal transcribed spacer 1 and 5.8S ribosomal RNA gene, complete sequence; and internal transcribed spacer 2, partial sequence
gi|614661938|gb|KF730103.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004605238	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20159562, 21127055, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004605238

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 24, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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 (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004605238.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Ser1063Argfs*15) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 187 amino acid(s) of the BRIP1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant disrupts the TopBP1-binding region of the BRIP1 protein, which plays a critical role in RPA chromatin loading and the activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). While functional studies have not been performed to directly test the effect of this variant on BRIP1 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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

Last Updated: Sep 29, 2024

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