rs786203717

chr17-61684050-CTCTT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_032043.3(BRIP1):c.2992_2995del(p.Lys998GlufsTer60) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K998K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: BRIP1 NM_032043.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16 U:1
• Conservation: PhyloP100: 1.14

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 Likely_pathogenic. Variant got 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 30 pathogenic variants in the truncated region.
• PP5: Variant 17-61684050-CTCTT-C is Pathogenic according to our data. Variant chr17-61684050-CTCTT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187416.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=14, Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.2992_2995del	p.Lys998GlufsTer60	frameshift_variant	20/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.2992_2995del	p.Lys998GlufsTer60	frameshift_variant	20/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251076 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135696

Gnomad AFR exome AF: 0.0000616

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: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1461590 Hom.: 0 AF XY: 0.0000206 AC XY: 15 AN XY: 727098

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74316

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:16 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Dec 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 03, 2023	Criteria applied: PVS1,PS3,PS4,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 28, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:4 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 24, 2021	The c.2992_2995delAAGA pathogenic mutation, located in coding exon 19 of the BRIP1 gene, results from a deletion of 4 nucleotides between positions 2992 and 2995, causing a translational frameshift with a predicted alternate stop codon. This mutation has been identified in early onset breast cancer and ovarian cancer patients (De Nicolo A et al. Clin. Cancer Res. 2008 Jul; 14(14):4672-80; Tedaldi G et al. Oncotarget 2017 Jul;8(29):47064-47075; Carter NJ et al. Gynecol Oncol. 2018 Dec;151(3):481-488). Functional analysis indicates that the premature truncation resulting from this alteration interferes with the stability of the protein and with its ability to interact with BRCA1 (De Nicolo A et al. Clin. Cancer Res. 2008 Jul; 14(14):4672-80). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 17, 2021	- -
Uncertain significance, criteria provided, single submitter	research	Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 06, 2022	This variant deletes 4 nucleotides 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). A functional study has shown that this variant affects protein stability and impairs interaction with BRCA1 (PMID: 18628483). This variant has been reported in multiple individuals affected with breast cancer or from a high risk family (PMID: 18628483, 26921362, 28423363, 29368626, 31325073). One of these individuals also carried a pathogenic variant in the BRCA2 gene (PMID: 28423363). This variant has been observed in multiple individuals affected with breast cancer or having a family history of breast, ovarian or colorectal cancer (Color internal data). This variant has been identified in 5/282468 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 20, 2019	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 12, 2023	This frameshift variant alters the translational reading frame of the BRIP1 mRNA and causes the premature termination of BRIP1 protein synthesis. The frequency of this variant in the general population, 0.000023 (3/129046 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in affected individuals with breast and/or ovarian cancer (PMID: 18628483 (2008), 26921362 (2016), 28423363 (2017), 29368626 (2018), 30322717 (2018), and 31325073 (2019)), as well as in an individual with acute myeloid leukemia (PMID: 33840814 (2021)). One functional study on transfected cells showed that the truncation interferes with the stability of the protein and with its ability to interact with BRCA1 (PMID: 18628483 (2008)), while another demonstrated reduced protein expression and BRCA1 binding disruption (PMID: 21345144 (2011)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2023	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 252 amino acids are lost and replaced with 59 incorrect amino acids; Published functional studies demonstrate a damaging effect: impaired protein stability and interaction with BRCA1 (De Nicolo et al., 2008); Observed in individuals with breast, ovarian, or renal cancer (De Nicolo et al., 2008; Easton et al., 2016; Tedaldi et al., 2017; Carter et al., 2018; Yngvadottir et al., 2022); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21345144, 26921362, 20159562, 18628483, 20346647, 29368626, 31325073, 34426522, 35441217, 29922827, 33840814, 28423363, 30322717) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

This sequence change creates a premature translational stop signal (p.Lys998Glufs*60) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 252 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs786203717, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 18628483, 26921362, 28423363). ClinVar contains an entry for this variant (Variation ID: 187416). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects BRIP1 function (PMID: 18628483, 20159562, 21127055, 21345144). This variant disrupts a region of the BRIP1 protein in which other variant(s) (p.Ser1070Glnfs*8) have been determined to be pathogenic (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 complementation group J Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 10, 2019

- -

Neoplasm of ovary;C1836860:Fanconi anemia complementation group J Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Apr 13, 2018

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 04, 2022

Variant summary: BRIP1 c.2992_2995delAAGA (p.Lys998GlufsX60) results in a premature termination codon causes a truncation of the encoded protein which is a commonly known mechanism for disease (De Nicolo_2008). Truncations downstream of this position have been observed at our laboratory and reported in association with other BRIP1-related cancers in the HGMD database. The variant allele was found at a frequency of 1.6e-05 in 251076 control chromosomes. c.2992_2995delAAGA has been reported in the literature among individuals with a variety of BRIP1-associated cancers such as breast/ovarian and AML (example, De Nicolo_2008, Tedaldi_2017, Carter_2018, Weber-Lassalle_2018, Wagener_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Di Nicolo_2008). The most pronounced variant effect impairs BRIP1 function and its ability to interact with BRCA1. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Aug 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs786203717; hg19: chr17-59761411;