rs774684620

chr17-61684098-AT-Achr17-61684098-AT-ATT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_032043.3(BRIP1):c.2947del(p.Ile983LeufsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,310 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRIP1 NM_032043.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.379

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 34 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-61684098-AT-A is Pathogenic according to our data. Variant chr17-61684098-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 461044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61684098-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.2947del	p.Ile983LeufsTer2	frameshift_variant	20/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.2947del	p.Ile983LeufsTer2	frameshift_variant	20/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250646 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135492

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461310 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2022	This variant deletes 1 nucleotide in exon 20 of the BRIP1 gene, creating a frameshift at codon 983 and premature translation stop signal at codon 984 in the last exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncated protein that lacks the functional domains involved in BRCA1-binding, DNA damage and replication stress responses and attenuation of DNA damage tolerance pathway (PMID: 11301010, 14983014, 20159562, 20173781, 22792074). Although functional studies have not been reported for this variant, this variant is expected to impair important BRIP1 protein function. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250646 chromosomes 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variant is a single base pair deletion from exon 20 of the BRIP1 mRNA, causing a frameshift after codon 983 and this creates a premature translational stop signal 2 amino acid residues later. This variant is expected to disrupt BRIP1-BRCA1 interaction because affects the BRCA1-binding domain (residues 888-1063) of the BRIP1 protein (PMID: 21345144). Truncating variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant has been described in the international literature in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 461044). -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 02, 2022	The c.2947delA pathogenic mutation, located in coding exon 19 of the BRIP1 gene, results from a deletion of one nucleotide at nucleotide position 2947, causing a translational frameshift with a predicted alternate stop codon (p.I983Lfs*2). This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 267 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration was detected in an individual diagnosed with breast cancer at age 46 who had a family history of breast cancer (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration was also seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 1/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 07, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

This sequence change creates a premature translational stop signal (p.Ile983Leufs*2) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 267 amino acid(s) of the BRIP1 protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 461044). This variant disrupts a region of the BRIP1 protein in which other variant(s) (p.Thr997Argfs*61, p.Lys998Glufs*60, p.Lys998Glufs*3) have been determined to be pathogenic (PMID: 18628483; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Fanconi anemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 26, 2022

The p.Ile983LeufsX2 variant in BRIP1 Reported in 2 breast cancer patients (Siraj 2017 PMID: 28975465) and 1 pt with hereditary breast cancer (with a family history of breast cancer) (Lerner-Ellis 2021 PMID: 32885271).This variant is absent in large population databases gnomad chromosomes by gnomAD. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 983 and leads to a premature termination codon 2 amino acids downstream. This alteration is in the last exon and is expected to evade nonsense-mediated decay (NMD); however, the variant impacts a region of the protein critical to its function (Gong 2010 PMID: 20159562, Xie 2012 PMID: 22792074) and several downstream missense variant have been associated with predisposition to cancer. Loss of function of the BRIP1 gene is an established disease mechanism in autosomal dominant cancer predisposition syndrome and autosomal recessive fanconi anemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant cancer predisposition syndrome and for autosomal recessive fanconi anemia. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PS4_Supporting. -

Fanconi anemia complementation group J Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 28, 2022

- -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

curation

Leiden Open Variation Database

Dec 23, 2019

Curator: Arleen D. Auerbach. Submitter to LOVD: Florentia Fostira. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRIP1 c.2947del variant was not identified in the literature nor was it identified in the dbSNP. The variant was identified ClinVar (classified pathogenic by Invitae and /likely pathogenic by GeneKor MSA). The variant was identified in control databases in 1 of 250646 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 113472 chromosomes (freq. 0.00001), while the variant was not observed in the African, Other, South Asian, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The c.2947del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 983 and leads to a premature stop codon at position 984. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRIP1 gene are an established mechanism of disease in BRIP1 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Breast carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 12, 2021

Diagnosis: Breast Cancer Pathology: Invasive Ductal Ca IHC: ER:+, PR:+, HER2:-, Ecadherin:+ Ki67:%20 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs774684620; hg19: chr17-59761459;