rs774684620

Variant names:

• chr17-61684098-AT-A
• rs774684620
• NM_032043.3:c.2947delA

Your query was ambiguous. Multiple possible variants found:

• chr17-61684098-AT-A
• chr17-61684098-AT-ATT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_032043.3(BRIP1):​c.2947delA​(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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRIP1 NM_032043.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:1
• Conservation: PhyloP100: 0.379
• Publications: 7 publications found

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]

BRIP1 Gene-Disease associations (from GenCC):

• familial ovarian cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• Fanconi anemia complementation group J

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary breast carcinoma

  Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 67 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 461044.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.2947delA	p.Ile983LeufsTer2	frameshift_variant	Exon 20 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.2947delA	p.Ile983LeufsTer2	frameshift_variant	Exon 20 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250646 AF XY: 0.00000738

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111820

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2 Uncertain:1

Jan 01, 2020

GeneKor MSA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Jun 17, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2947delA variant, 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 BRIP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 266 amino acids of the protein. The exact functional impact of these removed amino acids is unknown. While the C-terminal region of the BRIP1 protein has been shown by structural, biochemical, and mutational analysis to be relevant for some aspects of BRIP1 protein function (Gong Z et al. Mol. Cell, 2010 Feb;37:438-46; Leung CC et al. J. Biol. Chem. 2011 Feb; 286(6):4292-301; Xie J et al. PLoS Genet. 2012 Jul; 8(7):e1002786), functional studies have shown that truncations in the 3' terminus of BRIP1 display normal function in response to intra-strand cross-linking agents (Calvo JA et al. Mol Cancer Res, 2021 Jun;19:1015-1025). Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided Pathogenic:2

Jul 31, 2024

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2019

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

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

Familial cancer of breast Pathogenic:2

Jun 07, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Feb 07, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). 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

Aug 26, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 28, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Aug 12, 2021

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38
Mutation Taster		=10/190	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs774684620; hg19: chr17-59761459;