rs1555573327

chr17-61685948-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_032043.3(BRIP1):c.2792del(p.Pro931GlnfsTer54) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRIP1 NM_032043.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.56

Genes affected

BRIP1 (HGNC:20473): (BRCA1 interacting helicase 1) The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 48 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-61685948-TG-T is Pathogenic according to our data. Variant chr17-61685948-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 530293.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.2792del	p.Pro931GlnfsTer54	frameshift_variant	19/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.2792del	p.Pro931GlnfsTer54	frameshift_variant	19/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 16, 2017

This variant disrupts a significant C-terminal portion of the BRIP1 protein. It is expected to disrupt the BRCA1-binding domain (residues 888-1063) and the TopBP1-binding region (residues 1130-1153), which are both critical to BRIP1 function (PMID: 21345144, 20159562, 21127055). Although functional studies have not been performed for this particular variant, the downstream c.2992_2995delAAGA (p.Lys998Glufs*60) variant resulted in reduced protein stability and impaired BRCA1 interaction (PMID: 18628483) and has been determined to be pathogenic (PMID: 21345144, 20159562, 21127055). This suggests that disruption of this region of the BRIP1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with BRIP1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the BRIP1 gene (p.Pro931Glnfs*54). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 319 amino acids of the BRIP1 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555573327; hg19: chr17-59763309;