NM_032043.3(BRIP1):c.3651G>T (p.Trp1217Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 26, 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:: RCV000129907.21

Allele description [Variation Report for NM_032043.3(BRIP1):c.3651G>T (p.Trp1217Cys)]

NM_032043.3(BRIP1):c.3651G>T (p.Trp1217Cys)

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.3651G>T (p.Trp1217Cys)

HGVS:

NC_000017.11:g.61683395C>A
NG_007409.2:g.185165G>T
NM_032043.3:c.3651G>TMANE SELECT
NP_114432.2:p.Trp1217Cys
NP_114432.2:p.Trp1217Cys
LRG_300t1:c.3651G>T
LRG_300:g.185165G>T
LRG_300p1:p.Trp1217Cys
NC_000017.10:g.59760756C>A
NM_032043.2:c.3651G>T
p.W1217C

Protein change:

W1217C

Links:

dbSNP: rs542698396

NCBI 1000 Genomes Browser:

rs542698396

Molecular consequence:

NM_032043.3:c.3651G>T - 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
SCV000184725	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jul 26, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26976419, 28640387, 33606809, 35264596 Citation Link,
SCV000911032	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 23, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26976419, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184725

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jul 26, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000911032

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 23, 2023)

germline

clinical testing

PubMed (2)
[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

DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer.

Ricker CN, Hanna DL, Peng C, Nguyen NT, Stern MC, Schmit SL, Idos GE, Patel R, Tsai S, Ramirez V, Lin S, Shamasunadara V, Barzi A, Lenz HJ, Figueiredo JC.

Cancer. 2017 Oct 1;123(19):3732-3743. doi: 10.1002/cncr.30790. Epub 2017 Jun 22.

PubMed [citation]

PMID:: 28640387
PMCID:: PMC5610604

Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis.

Sandoval RL, Leite ACR, Barbalho DM, Assad DX, Barroso R, Polidorio N, Dos Anjos CH, de Miranda AD, Ferreira ACSM, Fernandes GDS, Achatz MI.

PLoS One. 2021;16(2):e0247363. doi: 10.1371/journal.pone.0247363.

PubMed [citation]

PMID:: 33606809
PMCID:: PMC7895369

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000184725.9

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

Description

The p.W1217C variant (also known as c.3651G>T), located in coding exon 19 of the BRIP1 gene, results from a G to T substitution at nucleotide position 3651. The tryptophan at codon 1217 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a cohort of 488 patients with breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). This alteration was detected in two different cohorts of Brazilian breast cancer patients (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This alteration was also detected in a patient with colorectal cancer who was also found to carry a pathogenic mutation in the MSH2 gene (Ricker CN et al. Cancer, 2017 Oct;123:3732-3743). This amino acid position is poorly 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, SCV000911032.5

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

Description

This missense variant replaces tryptophan with cysteine at codon 1217 of the BRIP1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with breast cancer (PMID: 26976419). This variant has been identified in 2/250810 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: Jan 19, 2025

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