NM_032043.3(BRIP1):c.1628+5G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: May 31, 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:: RCV000572734.12

Allele description [Variation Report for NM_032043.3(BRIP1):c.1628+5G>A]

NM_032043.3(BRIP1):c.1628+5G>A

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

17q23.2

Genomic location:

Preferred name:

NM_032043.3(BRIP1):c.1628+5G>A

HGVS:

NC_000017.11:g.61784265C>T
NG_007409.2:g.84295G>A
NM_032043.3:c.1628+5G>AMANE SELECT
LRG_300t1:c.1628+5G>A
LRG_300:g.84295G>A
NC_000017.10:g.59861626C>T
NM_032043.2:c.1628+5G>A

Links:

dbSNP: rs754929230

NCBI 1000 Genomes Browser:

rs754929230

Molecular consequence:

NM_032043.3:c.1628+5G>A - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000668875	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (May 31, 2023)	germline	clinical testing	Citation Link,
SCV000684145	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 30, 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

SCV000668875

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(May 31, 2023)

germline

clinical testing

Citation Link,

SCV000684145

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 30, 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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV000668875.6

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

Description

The c.1628+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 10 in the BRIP1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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

From Color Diagnostics, LLC DBA Color Health, SCV000684145.5

#	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 a G to A nucleotide substitution at the +5 position of intron 11 of the BRIP1 gene. A study using RNA from carrier-derived cells has reported that this variant leads to the skipping of exon 11, creating a premature translation stop signal in the RNA transcript (Leiden Open Variation Database (LOVD) variant number: 0000115868). The aberrant transcript is expected to result in an absent or non-functional protein product. Abnormal RNA splicing resulting from this variant has also been reported in ClinVar (ClinVar variation ID: 461078; communication with an external laboratory). This variant has been reported in individuals affected with ovarian cancer or breast cancer (LOVD; Color internal data). This variant has been identified in 1/251154 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

Last Updated: Sep 29, 2024

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