NM_032043.3(BRIP1):c.3386_3387del (p.Ser1129fs) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 28, 2020
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:: RCV001379350.8

Allele description [Variation Report for NM_032043.3(BRIP1):c.3386_3387del (p.Ser1129fs)]

NM_032043.3(BRIP1):c.3386_3387del (p.Ser1129fs)

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.3386_3387del (p.Ser1129fs)

HGVS:

NC_000017.11:g.61683660_61683661del
NG_007409.2:g.184900_184901del
NM_032043.3:c.3386_3387delMANE SELECT
NP_114432.2:p.Ser1129fs
LRG_300:g.184900_184901del
NC_000017.10:g.59761020_59761021del
NC_000017.10:g.59761021_59761022del

Protein change:

S1129fs

Links:

dbSNP: rs2144077998

NCBI 1000 Genomes Browser:

rs2144077998

Molecular consequence:

NM_032043.3:c.3386_3387del - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001577136	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 28, 2020)	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

SCV001577136

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 28, 2020)

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, SCV001577136.4

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

Description

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. This truncation affects the TopBP1-binding region (residues 1130-1153) of the BRIP1 protein. It is expected to disrupt the TopBP1-BRIP1 interaction that plays a critical role on RPA chromatin loading following DNA replication stress and the subsequent activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). This variant has not been reported in the literature in individuals with BRIP1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the BRIP1 gene (p.Ser1129Tyrfs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 121 amino acids of the BRIP1 protein.

#	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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