NM_032043.3(BRIP1):c.3370_3371del (p.Glu1124fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Dec 13, 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:: RCV000774184.8

Allele description [Variation Report for NM_032043.3(BRIP1):c.3370_3371del (p.Glu1124fs)]

NM_032043.3(BRIP1):c.3370_3371del (p.Glu1124fs)

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.3370_3371del (p.Glu1124fs)

HGVS:

NC_000017.11:g.61683676_61683677del
NG_007409.2:g.184884_184885del
NM_032043.3:c.3370_3371delMANE SELECT
NP_114432.2:p.Glu1124fs
NP_114432.2:p.Glu1124fs
LRG_300t1:c.3370_3371del
LRG_300:g.184884_184885del
LRG_300p1:p.Glu1124fs
NC_000017.10:g.59761036_59761037del
NC_000017.10:g.59761037_59761038del
NM_032043.2:c.3370_3371del
NM_032043.2:c.3370_3371delGA

Protein change:

E1124fs

Links:

dbSNP: rs1426528935

NCBI 1000 Genomes Browser:

rs1426528935

Molecular consequence:

NM_032043.3:c.3370_3371del - 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
SCV000907885	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 7, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20159562, 21127055, 22792074, 25741868
SCV002615534	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Dec 13, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000907885

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 7, 2023)

germline

clinical testing

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

SCV002615534

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Dec 13, 2023)

germline

clinical testing

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 (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000907885.3

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

Description

This variant deletes 2 nucleotides in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncated protein with last 123 amino acids of the protein replaced with 3 novel amino acids. The truncated protein is expected to have a disrupted TopBP1 binding domain (a.a. 1106-1178) and an acetylation site (p.Lys1249) in the C-terminus of the BRIP1 protein, which have been reported to play an important role in DNA replication-stress response and maintaining genomic stability (PMID: 20159562, 21127055, 22792074). To our knowledge, this variant has not been reported in individuals affected with BRIP1-related conditions in the literature. This variant has been identified in 1/250642 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple truncation variants that occur downstream of this variant are reported as disease-causing in ClinVar (e.g. c.3390_3393del (p.Tyr1131Leufs*18), ClinVar variation ID: 229712). Although the exact mechanism by which this variant causes disease is yet to be determined, the available evidence indicates that this variant is likely to disrupt normal BRIP1 protein function. Therefore, 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, SCV002615534.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The c.3370_3371delGA variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of two nucleotides at nucleotide positions 3370 to 3371, causing a translational frameshift with a predicted alternate stop codon (p.E1124Sfs*4). This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 123 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time; however, structural and functional studies 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(104):ra3; Xie J et al. PLoS Genet. Jul 2012; 8(7): e1002786). 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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