NM_032043.3(BRIP1):c.3374_3376del (p.Ala1125del) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 3, 2022
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:: RCV001020125.10

Allele description [Variation Report for NM_032043.3(BRIP1):c.3374_3376del (p.Ala1125del)]

NM_032043.3(BRIP1):c.3374_3376del (p.Ala1125del)

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.3374_3376del (p.Ala1125del)

HGVS:

NC_000017.11:g.61683672_61683674del
NG_007409.2:g.184888_184890del
NM_032043.3:c.3374_3376delMANE SELECT
NP_114432.2:p.Ala1125del
NP_114432.2:p.Ala1125del
LRG_300t1:c.3374_3376del
LRG_300:g.184888_184890del
LRG_300p1:p.Ala1125del
NC_000017.10:g.59761031_59761033del
NC_000017.10:g.59761033_59761035del
NM_032043.2:c.3374_3376del
NM_032043.2:c.3374_3376delCAG
NM_032043.3:c.3374_3376delCAGMANE SELECT

Protein change:

A1125del

Links:

dbSNP: rs745344948

NCBI 1000 Genomes Browser:

rs745344948

Molecular consequence:

NM_032043.3:c.3374_3376del - inframe_deletion - [Sequence Ontology: SO:0001822]

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
SCV001181562	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 3, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26921362, 32885271 Citation Link,
SCV001339554	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001181562

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 3, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001339554

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 5, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.

Easton DF, Lesueur F, Decker B, Michailidou K, Li J, Allen J, Luccarini C, Pooley KA, Shah M, Bolla MK, Wang Q, Dennis J, Ahmad J, Thompson ER, Damiola F, Pertesi M, Voegele C, Mebirouk N, Robinot N, Durand G, Forey N, Luben RN, et al.

J Med Genet. 2016 May;53(5):298-309. doi: 10.1136/jmedgenet-2015-103529. Epub 2016 Feb 26.

PubMed [citation]

PMID:: 26921362
PMCID:: PMC4938802

Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario.

Lerner-Ellis J, Mighton C, Lazaro C, Watkins N, Di Gioacchino V, Wong A, Chang MC, Charames GS.

J Cancer Res Clin Oncol. 2021 Mar;147(3):871-879. doi: 10.1007/s00432-020-03377-6. Epub 2020 Sep 3. Erratum in: J Cancer Res Clin Oncol. 2021 Aug;147(8):2487. doi: 10.1007/s00432-020-03399-0.

PubMed [citation]

PMID:: 32885271

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV001181562.4

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

Description

The c.3374_3376delCAG variant (also known as p.A1125del) is located in coding exon 19 of the BRIP1 gene. This variant results from an in-frame CAG deletion at nucleotide positions 3374 to 3376. This results in the in-frame deletion of an alanine at codon 1125. This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879) but was only present in control individuals in another breast cancer case-control study (Easton DF et al. J Med Genet, 2016 05;53:298-309). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). 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

From Color Diagnostics, LLC DBA Color Health, SCV001339554.2

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

Description

This variant causes an in-frame deletion of 1 amino acid of the BRIP1 protein. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 14/250592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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: Oct 8, 2024

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