NM_032043.3(BRIP1):c.3401del (p.Pro1134fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jul 10, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000772027.9

Allele description [Variation Report for NM_032043.3(BRIP1):c.3401del (p.Pro1134fs)]

NM_032043.3(BRIP1):c.3401del (p.Pro1134fs)

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.3401del (p.Pro1134fs)

HGVS:

NC_000017.11:g.61683646del
NG_007409.2:g.184915del
NM_032043.3:c.3401delMANE SELECT
NP_114432.2:p.Pro1134fs
NP_114432.2:p.Pro1134fs
LRG_300t1:c.3401del
LRG_300:g.184915del
LRG_300p1:p.Pro1134fs
NC_000017.10:g.59761006del
NC_000017.10:g.59761007del
NM_032043.2:c.3401del
NM_032043.2:c.3401delC

Protein change:

P1134fs

Links:

dbSNP: rs756853672

NCBI 1000 Genomes Browser:

rs756853672

Molecular consequence:

NM_032043.3:c.3401del - 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
SCV000904989	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 4, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16280053, 20159562, 20616022, 21127055, 22792074, 26315354, 35441217, 25741868
SCV001181660	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jul 10, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26921362, 35441217 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000904989

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 4, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV001181660

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jul 10, 2023)

germline

clinical testing

PubMed (2)
[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

Mutation analysis of FANCD2, BRIP1/BACH1, LMO4 and SFN in familial breast cancer.

Lewis AG, Flanagan J, Marsh A, Pupo GM, Mann G, Spurdle AB, Lindeman GJ, Visvader JE, Brown MA, Chenevix-Trench G; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer..

Breast Cancer Res. 2005;7(6):R1005-16. Epub 2005 Oct 21.

PubMed [citation]

PMID:: 16280053
PMCID:: PMC1410737

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

See all PubMed Citations (9)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000904989.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This variant deletes 1 nucleotide in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last coding exon. The mutant transcript is expected to escape nonsense-mediated decay and expressed as a truncated protein that lacks the last 100 amino acids of the protein. The truncated protein is expected to disrupt the TopBP1 binding domain (a.a. 1106-1178) and 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 with breast or ovarian cancer (PMID: 16280053, 20616022), renal cell carcinoma (PMID: 35441217), and in an unaffected control subject (PMID: 26315354). This variant has been identified in 3/250050 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, SCV001181660.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.3401delC variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of one nucleotide at nucleotide position 3401, causing a translational frameshift with a predicted alternate stop codon (p.P1134Lfs*16). This alteration has been reported in individuals with breast and/or ovarian cancer and well as an individual with renal cell carcinoma (Lewis AG et al. Breast Cancer Res. 2005 Oct;7(6):R1005-16; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2010 Jul;107(28):12629-33; Easton DF et al. J Med Genet, 2016 May;53:298-309; Yngvadottir B et al. Hum Mol Genet, 2022 Aug;31:3001-3011). One computational model showed no significant effect on mRNA structure as a result of this variant (Lewis AG et al. Breast Cancer Res. 2005 Oct;7(6):R1005-16). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 100 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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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