NM_032043.3(BRIP1):c.2244C>G (p.Tyr748Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 21, 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:: RCV000576013.5

Allele description [Variation Report for NM_032043.3(BRIP1):c.2244C>G (p.Tyr748Ter)]

NM_032043.3(BRIP1):c.2244C>G (p.Tyr748Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

17q23.2

Genomic location:

Preferred name:

NM_032043.3(BRIP1):c.2244C>G (p.Tyr748Ter)

HGVS:

NC_000017.11:g.61744445G>C
NG_007409.2:g.124115C>G
NM_032043.3:c.2244C>GMANE SELECT
NP_114432.2:p.Tyr748Ter
NP_114432.2:p.Tyr748Ter
LRG_300t1:c.2244C>G
LRG_300:g.124115C>G
LRG_300p1:p.Tyr748Ter
NC_000017.10:g.59821806G>C
NM_032043.2:c.2244C>G

Protein change:

Y748*

Links:

dbSNP: rs1257401983

NCBI 1000 Genomes Browser:

rs1257401983

Molecular consequence:

NM_032043.3:c.2244C>G - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000661520	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 5, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004362913	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 21, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28961279, 29566657, 31742824, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000661520

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Aug 5, 2022)

germline

clinical testing

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

Citation Link,

SCV004362913

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 21, 2022)

germline

clinical testing

PubMed (4)
[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

The frequency of cancer predisposition gene mutations in hereditary breast and ovarian cancer patients in Taiwan: From BRCA1/2 to multi-gene panels.

Sung PL, Wen KC, Chen YJ, Chao TC, Tsai YF, Tseng LM, Qiu JT, Chao KC, Wu HH, Chuang CM, Wang PH, Huang CF.

PLoS One. 2017;12(9):e0185615. doi: 10.1371/journal.pone.0185615.

PubMed [citation]

PMID:: 28961279
PMCID:: PMC5621677

Germline breast cancer susceptibility gene mutations and breast cancer outcomes.

Wang YA, Jian JW, Hung CF, Peng HP, Yang CF, Cheng HS, Yang AS.

BMC Cancer. 2018 Mar 22;18(1):315. doi: 10.1186/s12885-018-4229-5.

PubMed [citation]

PMID:: 29566657
PMCID:: PMC5863855

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000661520.5

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

Description

The p.Y748* pathogenic mutation (also known as c.2244C>G), located in coding exon 14 of the BRIP1 gene, results from a C to G substitution at nucleotide position 2244. This changes the amino acid from a tyrosine to a stop codon within coding exon 14. This alteration has been previously reported in an individual with primary peritoneal serous carcinoma (Sung PL et al. PLoS ONE, 2017 Sep;12:e0185615). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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, SCV004362913.1

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

Description

This variant changes 1 nucleotide in exon 15 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast, ovarian, and peritoneal cancer in the literature (PMID: 28961279, 29566657, 31742824). This variant has not been identified 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 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 8, 2024

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