rs786204259

Variant names:

• chr17-61683669-TCTG-T
• rs745344948
• NM_032043.3:c.3374_3376delCAG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_032043.3(BRIP1):​c.3374_3376delCAG​(p.Ala1125del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000235 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: BRIP1 NM_032043.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9 O:1
• Conservation: PhyloP100: 4.82
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_032043.3. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.3374_3376delCAG	p.Ala1125del	disruptive_inframe_deletion	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.3374_3376delCAG	p.Ala1125del	disruptive_inframe_deletion	Exon 20 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000559 AC: 14 AN: 250592 AF XY: 0.0000516

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: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461238 Hom.: 0 AF XY: 0.0000248 AC XY: 18 AN XY: 726930

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111966

Other (OTH) AF: 0.000182 AC: 11 AN: 60386

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74520

African (AFR) AF: 0.00 AC: 0 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Nov 06, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.3374_3376del, located in exon 20 of the BRIP1 gene, consists in the deletion of 3 nucleotides, predicted to cause an in-frame deletion of 1 amino acid p.(Ala1125del).This variant is found in 14/267468 alleles at a frequency of 0.005% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing . To our knowledge, neither relevant clinical data nor well-established functional studies have been reported for this variant. It has been reported in a breast cancer-affected patient (PMID:32885271). It has also been reported in 2 out of 5242 controls and none of 13,213 breast cancer patients (PMID: 26921362). This variant has been reported in the ClinVar database (7x uncertain significance) and has not been reported in LOVD. Based on currently available information, the variant c.3374_3376del should be considered an uncertain significance variant, according to ACMG/AMP classification guidelines. -

Jan 05, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an in-frame deletion of 1 amino acid of the BRIP1 protein. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 14/250592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jul 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3374_3376delCAG variant (also known as p.A1125del) is located in coding exon 19 of the BRIP1 gene. This variant results from an in-frame CAG deletion at nucleotide positions 3374 to 3376. This results in the in-frame deletion of an alanine at codon 1125. This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879) but was only present in control individuals in another breast cancer case-control study (Easton DF et al. J Med Genet, 2016 05;53:298-309). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Uncertain:1

Apr 14, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.3374_3376del, results in the deletion of 1 amino acid(s) of the BRIP1 protein (p.Ala1125del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs745344948, gnomAD 0.01%). 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: 188402). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Apr 09, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Observed in individuals with a personal and family history of breast and/or ovarian cancer, as well as in unaffected control groups (PMID: 32885271, 26921362); This variant is associated with the following publications: (PMID: 32885271, 26921362) -

Familial ovarian cancer Uncertain:1

Apr 22, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRIP1 p.Ala1125del variant was not identified in the literature. The variant was identified in dbSNP (ID: rs745344948) as "With Uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae and GeneDx). The variant was identified in control databases in 14 of 245568 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 14 of 111430 chromosomes (freq: 0.0001), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, Latino, Other, or South Asian populations. This variant is an in-frame deletion resulting in the removal of Alanine (Ala) residue at codon 1125; the impact of this alteration on BRIP1 protein function is not known. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

BRIP1-related disorder Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 06-09-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs745344948; hg19: chr17-59761030;