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NM_032043.3(BRIP1):c.2992_2993del (p.Lys998fs) AND Hereditary breast ovarian cancer syndrome

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Feb 2, 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:
RCV001293609.4

Allele description [Variation Report for NM_032043.3(BRIP1):c.2992_2993del (p.Lys998fs)]

NM_032043.3(BRIP1):c.2992_2993del (p.Lys998fs)

Gene:
BRIP1:BRCA1 interacting DNA helicase 1 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
17q23.2
Genomic location:
Preferred name:
NM_032043.3(BRIP1):c.2992_2993del (p.Lys998fs)
HGVS:
  • NC_000017.11:g.61684054_61684055del
  • NG_007409.2:g.184506_184507del
  • NM_032043.3:c.2992_2993delMANE SELECT
  • NP_114432.2:p.Lys998fs
  • LRG_300:g.184506_184507del
  • NC_000017.10:g.59761414_59761415del
  • NC_000017.10:g.59761415_59761416del
  • NC_000017.11:g.61684053_61684054delTT
  • NM_032043.2:c.2992_2993delAA
  • NM_032043.3:c.2992_2993del
Links:
dbSNP: rs878855151
NCBI 1000 Genomes Browser:
rs878855151
Molecular consequence:
  • NM_032043.3:c.2992_2993del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Hereditary breast ovarian cancer syndrome
Synonyms:
Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001482227Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Feb 5, 2021)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV004848895Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 2, 2023)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer.

Maxwell KN, Wubbenhorst B, D'Andrea K, Garman B, Long JM, Powers J, Rathbun K, Stopfer JE, Zhu J, Bradbury AR, Simon MS, DeMichele A, Domchek SM, Nathanson KL.

Genet Med. 2015 Aug;17(8):630-8. doi: 10.1038/gim.2014.176. Epub 2014 Dec 11.

PubMed [citation]
PMID:
25503501
PMCID:
PMC4465412

Panel Testing for Familial Breast Cancer: Calibrating the Tension Between Research and Clinical Care.

Thompson ER, Rowley SM, Li N, McInerny S, Devereux L, Wong-Brown MW, Trainer AH, Mitchell G, Scott RJ, James PA, Campbell IG.

J Clin Oncol. 2016 May 1;34(13):1455-9. doi: 10.1200/JCO.2015.63.7454. Epub 2016 Jan 19.

PubMed [citation]
PMID:
26786923
See all PubMed Citations (8)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001482227.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Variant summary: BRIP1 c.2992_2993delAA (p.Lys998GlufsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.3e-05 in 265460 control chromosomes (gnomAD and publications). c.2992_2993delAA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Maxwell_2015, Lilyquist_2017, Nassar_2020), while it has also been reported in an unaffected individual with a family history of breast cancer (Mersch_2018) and in healthy controls (e.g. Easton_2016, Thompson_2016, FLOSSIES database). These data indicate that the variant may be associated with disease. A co-occurrence with another pathogenic variant has been reported in a breast cancer patient (BRCA1 c.68_69delAG, p.Glu23ValfsX17; Kadri_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Other frameshift variants in this region of the BRIP1 gene are cited in HGMD and ClinVar databases as disease-associated/pathogenic (e.g. c.2990_2993delCAAA, p.Thr997ArgfsX61; c.2992_2995delAAGA, p.Lys998GlufsX60). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848895.1

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

Description

The p.Lys998GlufsX3 variant in BRIP1 has been reported in 1 individual from an ovarian cancer cohort (Lilyquist 2017 PMID: 28888541) and was absent in large population databases. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 998 and leads to a premature termination codon 3 amino acids downstream. The variant occurs in the last exon and may escape mRNA nonsense mediated decay; however it's predicted to remove ~20% of the protein impacting the c-terminus region which is critical for protein function (Leung 2011 PMID: 21127055, Gong 2010 PMID: 20159562). Other frameshift variants at the same codon (c.2992_2995delAAGA, p.Lys998Glufs*60) or downstream of this variant has been reported in individuals with ovarian breast cancer. Loss of function of BRIP1 is an established disease mechanism for autosomal dominant ovarian cancer and autosomal recessive Fanconi anemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ovarian cancer and autosomal recessive Fanconi anemia. ACMG/AMP criteria applied: PVS1_Strong, PM1, PM2_Supporting.

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

Last Updated: Feb 1, 2025