17-61684098-AT-ATT

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_032043.3(BRIP1):​c.2947dupA​(p.Ile983AsnfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,492 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BRIP1 NM_032043.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 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: Likely_pathogenic. The variant received 9 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.
• PP5: Variant 17-61684098-A-AT is Pathogenic according to our data. Variant chr17-61684098-A-AT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 407863.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032043.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	NM_032043.3	MANE Select	c.2947dupA	p.Ile983AsnfsTer19	frameshift	Exon 20 of 20	NP_114432.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	ENST00000259008.7	TSL:1 MANE Select	c.2947dupA	p.Ile983AsnfsTer19	frameshift	Exon 20 of 20	ENSP00000259008.2
	BRIP1	ENST00000682453.1		c.2947dupA	p.Ile983AsnfsTer19	frameshift	Exon 21 of 21	ENSP00000506943.1
	BRIP1	ENST00000683039.1		c.2947dupA	p.Ile983AsnfsTer19	frameshift	Exon 21 of 21	ENSP00000508303.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152064 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: 0.00

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250646 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.00000411 AC: 6 AN: 1461310 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726946

African (AFR) AF: 0.0000598 AC: 2 AN: 33432

American (AMR) AF: 0.0000224 AC: 1 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: 0.0000116 AC: 1 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 AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74426

African (AFR) AF: 0.00 AC: 0 AN: 41512

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Pathogenic:2

Jul 30, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

Jun 07, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: flagged submission

Collection Method: clinical testing

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

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Jun 10, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal 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 been reported in an individual affected with breast cancer (PMID: 30093976). This variant has been identified in 2/250646 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.

Dec 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2947dupA variant, located in coding exon 19 of the BRIP1 gene, results from a duplication of A at nucleotide position 2947, causing a translational frameshift with a predicted alternate stop codon (p.I983Nfs*19). This alteration has been observed in individual(s) with a personal and/or family history of breast cancer (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Fostira F et al. J Med Genet, 2020 Jan;57:53-61; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 21% of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

Jul 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BRIP1 protein in which other variant(s) (p.Lys998Glufs*60) have been determined to be pathogenic (PMID: 18628483, 21345144; 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. ClinVar contains an entry for this variant (Variation ID: 407863). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is present in population databases (rs774684620, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Ile983Asnfs*19) 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38
Mutation Taster		=6/194	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; COSMIC: COSV51994698;