NM_032043.3(BRIP1):c.2344A>G (p.Ile782Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 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:: RCV000131421.19

Allele description [Variation Report for NM_032043.3(BRIP1):c.2344A>G (p.Ile782Val)]

NM_032043.3(BRIP1):c.2344A>G (p.Ile782Val)

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.2344A>G (p.Ile782Val)

HGVS:

NC_000017.11:g.61743048T>C
NG_007409.2:g.125512A>G
NM_032043.3:c.2344A>GMANE SELECT
NP_114432.2:p.Ile782Val
NP_114432.2:p.Ile782Val
LRG_300t1:c.2344A>G
LRG_300:g.125512A>G
LRG_300p1:p.Ile782Val
NC_000017.10:g.59820409T>C
NM_032043.2:c.2344A>G
p.I782V

Protein change:

I782V

Links:

dbSNP: rs142806416

NCBI 1000 Genomes Browser:

rs142806416

Molecular consequence:

NM_032043.3:c.2344A>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000186402	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 13, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26921362, 28767289, 31822495 Citation Link,
SCV001348315	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 13, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 28767289, 31822495, 32659497, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186402

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 13, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV001348315

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 13, 2023)

germline

clinical testing

PubMed (5)
[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

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

Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma.

Shindo K, Yu J, Suenaga M, Fesharakizadeh S, Cho C, Macgregor-Das A, Siddiqui A, Witmer PD, Tamura K, Song TJ, Navarro Almario JA, Brant A, Borges M, Ford M, Barkley T, He J, Weiss MJ, Wolfgang CL, Roberts NJ, Hruban RH, Klein AP, Goggins M.

J Clin Oncol. 2017 Oct 20;35(30):3382-3390. doi: 10.1200/JCO.2017.72.3502. Epub 2017 Aug 2.

PubMed [citation]

PMID:: 28767289
PMCID:: PMC5648172

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000186402.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.I782V variant (also known as c.2344A>G), located in coding exon 15 of the BRIP1 gene, results from an A to G substitution at nucleotide position 2344. The isoleucine at codon 782 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in cohorts of breast, pancreatic, and ovarian cancer patients, as well as in a control (Easton DF et al. J Med Genet, 2016 05;53:298-309; Shindo K et al. J. Clin Oncol, 2017 Oct;35:3382-3390; Moyer CL et al. Cancer Res, 2020 02;80:857-867). In an inter-strand cross link damage survival assay, the p.I782V alteration was found to be functionally hypomorphic (Moyer CL et al. Cancer Res, 2020 02;80:857-867). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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, SCV001348315.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces isoleucine with valine at codon 782 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has reported that this variant resulted in hymomorphic activity in a mitomycin C sensitivity assay (PMID: 31822495). This variant has been detected in individuals affected with pancreatic cancer (PMID: 28767289, 32659497) and in 10/101759 breast cancer and 1/15587 ovarian cancer cases (PMID: 31822495). This variant also has been reported in the general population (PMID: 31822495) and in 1 individual age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/17-59820409-T-C). A breast cancer case-control meta-study has been detected this variant in 3/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRIP1_000419). This variant has been identified in 2/251332 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 20, 2024

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