rs1555591385

Positions:

• chr17-61744483-C-CA

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.2205_2206insT​(p.Asp736Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRIP1 NM_032043.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.78

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-61744483-C-CA is Pathogenic according to our data. Variant chr17-61744483-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 546045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.2205_2206insT	p.Asp736Ter	frameshift_variant	15/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.2205_2206insT	p.Asp736Ter	frameshift_variant	15/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 14, 2022

For these reasons, this variant has been classified as Pathogenic. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 546045). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp736*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 05, 2016

This variant is denoted BRIP1 c.2205dupT at the cDNA level and p.Asp736Ter (D736X) at the protein level. The substitution creates a nonsense variant, which changes an Aspartic Acid to a premature stop codon (GAT>TGA) , and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered likely pathogenic. BRIP1 has been only recently described in association with cancer predisposition and the risks are not well understood. The presence of a BRIP1 pathogenic variant may confer an increased risk for female breast and ovarian cancer, and possibly pancreatic (Seal 2006, Rafnar 2011, Pennington 2014). In a case-control study of BRCA-negative women with breast cancer, truncating BRIP1 pathogenic variants were identified in 0.7% (9/1,212) women with breast cancer and 0.1% (2/2,081) controls, suggesting some increased breast cancer risk (OR = 2.0, p=0.012) (Seal 2006). Pennington et al. (2014) also identified germline BRIP1 pathogenic variants in 1.1% (4/367) patients with ovarian cancer, peritoneal cancer or fallopian tube cancer. It has been hypothesized that BRIP1 may be a low penetrance allele as families with multiple cases of breast cancer found to harbor a BRIP1 pathogenic variant have shown incomplete segregation with disease (Seal 2006). Fanconi anemia (FA) is a rare autosomal recessive condition that can be caused by two pathogenic variants (one in each copy of the gene) in the BRIP1 gene (Seal 2006). This condition is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy in children including leukemia and certain solid tumors. The Fanconi anemia phenotype due to BRIP1 pathogenic variants is thought to result in a lower rate of childhood solid tumors compared to the phenotype due to two BRCA2 pathogenic variants (Apostolou 2013). If both parents carry a BRIP1 pathogenic variant, the risk to have a child with FA is 25% for each pregnancy. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jun 06, 2023

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

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: rs1555591385; hg19: chr17-59821844;