17-61684052-CTTTG-CTTTGTTTG

Position:

• chr17-61684052-CTTTG-CTTTGTTTG

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.2990_2993dupCAAA​(p.Lys998fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,458 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRIP1 NM_032043.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.668

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 (HGNC:):

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 0.202 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 17-61684052-C-CTTTG is Pathogenic according to our data. Variant chr17-61684052-C-CTTTG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 241647.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.2990_2993dupCAAA	p.Lys998fs	frameshift_variant	20/20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.2990_2993dupCAAA	p.Lys998fs	frameshift_variant	20/20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461458 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727040

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

This sequence change creates a premature translational stop signal (p.Lys998Asnfs*5) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 241647). 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, 26921362, 28423363). 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. -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 11, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2024

The c.2990_2993dupCAAA pathogenic mutation, located in coding exon 19 of the BRIP1 gene, results from a duplication of CAAA at nucleotide position 2990, causing a translational frameshift with a predicted alternate stop codon (p.K998Nfs*5). This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 252 amino acids of the protein. 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 the protein function (Gong Z et al. Mol. Cell, 2010 Feb;37:438-46; Leung CC et al. J. Biol. Chem. 2011 Feb; 286(6):4292-301; Xie J et al. PLoS Genet. 2012 Jul; 8(7):e1002786). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 03, 2022

The p.Lys998AsnfsX5 variant in BRIP1 has been reported in at least 1 individual with breast or ovarian cancer and in 1 individual with a B-cell neoplasm (Shao 2020 PMID: 31742824, Mosquera Orgueira 2021 PMID: 33809641). It has also been reported in ClinVar (Variation ID 241647) but was absent from large population databases. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 998 and leads to a premature termination codon 5 amino acids downstream. This termination codon occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. It is predicted to disrupt the last 252 amino acids of the BRIP1 protein and several other BRIP1 variants located downstream of this variant have been reported in individuals with breast and or ovariant cancer. Loss of function of the BRIP1 gene is an established disease mechanism in autosomal dominant breast and ovariant cancer. In summary, In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant breast and ovarian cancer. ACMG/AMP Criteria applied: PVS1_Strong, PS4_Supporting, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs771028677; hg19: chr17-59761413;