rs1555572410

Positions:

• chr17-61683295-ATTAC-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_032043.3(BRIP1):​c.3747_3750del​(p.Lys1249AsnfsTer4) variant causes a frameshift, stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K1249K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRIP1 NM_032043.3 frameshift, stop_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.65

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 10 ACMG points.

• PVS1: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.3747_3750del	p.Lys1249AsnfsTer4	frameshift_variant, stop_lost	20/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.3747_3750del	p.Lys1249AsnfsTer4	frameshift_variant, stop_lost	20/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 01, 2020	The c.3747_3750delGTAA variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of 4 nucleotides at nucleotide positions 3747 to 3750, causing a translational frameshift with a predicted alternate stop codon (p.K1249Nfs*4). This nucleotide region is not well conserved in available vertebrate species. Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and results in the elongation of the protein by 2 amino acids. The exact functional impact of these inserted amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 25, 2019	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 22, 2022

This sequence change results in a frameshift in the BRIP1 gene (p.Lys1249Asnfs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1 amino acid(s) of the BRIP1 protein and extend the protein by 2 additional amino acid residues. 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: 530351). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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: rs1555572410; hg19: chr17-59760656;