NM_032043.3(BRIP1):c.3240dup (p.Ala1081fs) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 5, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001063687.10

Allele description [Variation Report for NM_032043.3(BRIP1):c.3240dup (p.Ala1081fs)]

NM_032043.3(BRIP1):c.3240dup (p.Ala1081fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

17q23.2

Genomic location:

Preferred name:

NM_032043.3(BRIP1):c.3240dup (p.Ala1081fs)

HGVS:

NC_000017.11:g.61683806dup
NG_007409.2:g.184754dup
NM_032043.3:c.3240dupMANE SELECT
NP_114432.2:p.Ala1081fs
NP_114432.2:p.Ala1081fs
LRG_300t1:c.3240dup
LRG_300:g.184754dup
LRG_300p1:p.Ala1081fs
NC_000017.10:g.59761166_59761167insA
NC_000017.10:g.59761167dup
NM_032043.2:c.3240dup
NM_032043.2:c.3240dupT

Protein change:

A1081fs

Links:

dbSNP: rs779741278

NCBI 1000 Genomes Browser:

rs779741278

Molecular consequence:

NM_032043.3:c.3240dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial; Hereditary breast cancer
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

Name:: Fanconi anemia complementation group J
Identifiers:: MONDO: MONDO:0012187; MedGen: C1836860; Orphanet: 84; OMIM: 609054

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001228546	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 5, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 27498913, 31214711, 20159562, 21127055, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001228546

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 5, 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

Monogenic and polygenic determinants of sarcoma risk: an international genetic study.

Ballinger ML, Goode DL, Ray-Coquard I, James PA, Mitchell G, Niedermayr E, Puri A, Schiffman JD, Dite GS, Cipponi A, Maki RG, Brohl AS, Myklebost O, Stratford EW, Lorenz S, Ahn SM, Ahn JH, Kim JE, Shanley S, Beshay V, Randall RL, Judson I, et al.

Lancet Oncol. 2016 Sep;17(9):1261-71. doi: 10.1016/S1470-2045(16)30147-4. Epub 2016 Aug 4.

PubMed [citation]

PMID:: 27498913

Germline Pathogenic Variants in 7636 Japanese Patients With Prostate Cancer and 12 366 Controls.

Momozawa Y, Iwasaki Y, Hirata M, Liu X, Kamatani Y, Takahashi A, Sugano K, Yoshida T, Murakami Y, Matsuda K, Nakagawa H, Spurdle AB, Kubo M.

J Natl Cancer Inst. 2020 Apr 1;112(4):369-376. doi: 10.1093/jnci/djz124.

PubMed [citation]

PMID:: 31214711
PMCID:: PMC7156928

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001228546.5

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

Description

This sequence change creates a premature translational stop signal (p.Ala1081Cysfs*5) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 169 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs779741278, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with sarcoma and prostate cancer (PMID: 27498913, 31214711). ClinVar contains an entry for this variant (Variation ID: 324348). This variant disrupts the TopBP1-binding region of the BRIP1 protein, which plays a critical role in RPA chromatin loading and the activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). While functional studies have not been performed to directly test the effect of this variant on BRIP1 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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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