chr17-61683718-C-A

Position:

• chr17-61683718-C-A

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.3328G>T​(p.Glu1110*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRIP1 NM_032043.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.0260

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. Fraction of 0.113 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-61683718-C-A is Pathogenic according to our data. Variant chr17-61683718-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 407865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.3328G>T	p.Glu1110*	stop_gained	20/20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.3328G>T	p.Glu1110*	stop_gained	20/20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461788 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727202

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 27, 2023	This variant changes 1 nucleotide in exon 20 of the BRIP1 gene, creating a premature translation stop signal at codon 1110. This variant is expected to escape nonsense-mediated decay and be expressed as a truncated protein that lacks the last 140 amino acids of the protein. The truncated protein is expected to disrupt the TopBP1 binding domain (a.a. 1106-1178) and an acetylation site (p.Lys1249) in the C-terminus, which have been reported to play an important role in DNA replication-stress response and maintaining genomic stability (PMID: 20159562, 21127055, 22792074). Although functional studies have not been reported for this variant, this variant is expected to impair important BRIP1 protein function. To our knowledge, this variant has not been reported in individuals affected with BRIP1-related disorders in the literature. This variant has not been identified 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 09, 2023	The p.E1110* variant (also known as c.3328G>T), located in coding exon 19 of the BRIP1 gene, results from a G to T substitution at nucleotide position 3328. This changes the amino acid from a glutamic acid to a stop codon within coding exon 19. This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 140 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the C-terminal region of the protein has been shown by structural, biochemical, and mutational analysis to be relevant for protein function (Leung CC et al. J. Biol. Chem. 2011 Feb; 286(6):4292-301. Xie J et al. PLoS Genet. 2012 Jul; 8(7):e1002786; Gong Z et al. Mol. Cell, 2010 Feb;37:438-46). This variant is also 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;C1836860:Fanconi anemia complementation group J Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 407865). 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.Glu1110*) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 140 amino acid(s) of the BRIP1 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	26
DANN	Benign	0.97
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.15	N
Vest4		0.59
GERP RS		-0.35

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: rs1060501774; hg19: chr17-59761079;