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NM_032043.3(BRIP1):c.1340+5G>C AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:
Jan 8, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV000210143.14

Allele description [Variation Report for NM_032043.3(BRIP1):c.1340+5G>C]

NM_032043.3(BRIP1):c.1340+5G>C

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.1340+5G>C
HGVS:
  • NC_000017.11:g.61799095C>G
  • NG_007409.2:g.69465G>C
  • NM_032043.3:c.1340+5G>CMANE SELECT
  • LRG_300t1:c.1340+5G>C
  • LRG_300:g.69465G>C
  • NC_000017.10:g.59876456C>G
  • NM_032043.2:c.1340+5G>C
Links:
dbSNP: rs869312791
NCBI 1000 Genomes Browser:
rs869312791
Molecular consequence:
  • NM_032043.3:c.1340+5G>C - intron variant - [Sequence Ontology: SO:0001627]
Observations:
1

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000266159University of Washington Department of Laboratory Medicine, University of Washington
criteria provided, single submitter

(Shirts et al. (Genet Med 2016))
Uncertain significance
(Nov 20, 2015)
germlineclinical testing

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

SCV000664824Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Uncertain significance
(Dec 12, 2023)
germlineclinical testing

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

Citation Link,

SCV000909783Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jan 8, 2024)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Improving performance of multigene panels for genomic analysis of cancer predisposition.

Shirts BH, Casadei S, Jacobson AL, Lee MK, Gulsuner S, Bennett RL, Miller M, Hall SA, Hampel H, Hisama FM, Naylor LV, Goetsch C, Leppig K, Tait JF, Scroggins SM, Turner EH, Livingston R, Salipante SJ, King MC, Walsh T, Pritchard CC.

Genet Med. 2016 Oct;18(10):974-81. doi: 10.1038/gim.2015.212. Epub 2016 Feb 4.

PubMed [citation]
PMID:
26845104

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 University of Washington Department of Laboratory Medicine, University of Washington, SCV000266159.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From Ambry Genetics, SCV000664824.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The c.1340+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 8 in the BRIP1 gene. This alteration has been detected in an individual diagnoses with ovarian cancer (Shirts BH et al. Genet Med, 2016 10;18:974-81). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV000909783.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This variant causes a G to C nucleotide substitution at the +5 position of intron 9 of the BRIP1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have shown that this variant allele causes intron 9 retention or exon 9 skipping, creating a premature translation stop signal in the RNA transcripts (unpublished targeted RNAseq data from the King Lab, 2017 ASHG cBROCA abstract 796W at https://www.ashg.org/wp-content/uploads/2019/10/2017-Poster-Abstracts.pdf). The aberrant transcripts are expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with ovarian cancer (PMID: 26845104; Color Health internal data). 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 Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 19, 2025