rs748598593

chr17-61683837-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_032043.3(BRIP1):c.3208del(p.Ser1070GlnfsTer8) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S1070S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRIP1 NM_032043.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.60

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 14 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 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-61683837-GA-G is Pathogenic according to our data. Variant chr17-61683837-GA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 461046.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.3208del	p.Ser1070GlnfsTer8	frameshift_variant	20/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.3208del	p.Ser1070GlnfsTer8	frameshift_variant	20/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2019	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 180 amino acids are lost and replaced with 7 incorrect amino acids (Stenson 2014); Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 26689913, 29922827) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 20, 2020	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Not found in the total gnomAD dataset, and the data is high quality. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

This sequence change creates a premature translational stop signal (p.Ser1070Glnfs*8) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 180 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs748598593, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and/or endometrial cancer (PMID: 28452373, 30914433, 36451132). ClinVar contains an entry for this variant (Variation ID: 461046). This variant disrupts the TopBP1-binding region of the BRIP1 protein, which plays a critical role in RPA chromatin loading and the activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). While functional studies have not been performed to directly test the effect of this variant on BRIP1 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2023

The c.3208delT variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of one nucleotide at nucleotide position 3208, causing a translational frameshift with a predicted alternate stop codon (p.S1070Qfs*8). Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 180 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, structural and functional analyses suggest that at least two residues contained in this deleted region (Ser1237 and Lys1249) have functional importance (Olsen JV et al. Sci Signal, 2010 Jan;3:ra3; Xie J et al. PLoS Genet., 2012 Jul;8:e1002786). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 10, 2023

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

May 18, 2023

Variant summary: BRIP1 c.3208delT (p.Ser1070GlnfsX8) results in a premature termination codon, and although it is not expected to undergo nonsense mediated decay, it is predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. The variant was absent in 251388 control chromosomes (gnomAD). c.3208delT has been reported in the literature in an individual affected with breast cancer and in an individual affected with endometrial cancer (Lu_2015, Kraya_2019). To our knowledge, no experimental evidence directly examining the impact of this variant on protein function has been reported. However, this variant disrupts the TopBP1-binding domain of the BRIP1 protein, including the C-terminal Thr1133 residue required for interaction with TopB1, which plays a critical role in DNA damage response (Gong_2010). The following publications have been ascertained in the context of this evaluation (PMID: 30914433, 26689913, 20159562). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs748598593; hg19: chr17-59761198;