rs876660100

Positions:

• chr17-61683625-CTTCAGGATCA-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_032043.3(BRIP1):​c.3411_3420delTGATCCTGAA​(p.Tyr1137fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y1137Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRIP1 NM_032043.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 5.00

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 Uncertain_significance. Variant got 5 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 0.0904 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 17-61683625-CTTCAGGATCA-C is Pathogenic according to our data. Variant chr17-61683625-CTTCAGGATCA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 232964.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.3411_3420delTGATCCTGAA	p.Tyr1137fs	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.3411_3420delTGATCCTGAA	p.Tyr1137fs	frameshift_variant	20/20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2017

The c.3411_3420del10 variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of 10 nucleotides between nucleotide positions 3411 and 3420, causing a translational frameshift with a predicted alternate stop codon. Frameshifts are typically deleterious in nature, however, this deletion and subsequent frameshift occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense mediated decay (NMD), and results in the removal of only the last 112 amino acids of the protein. Structural and functional studies 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(104):ra3; Xie J et al. PLoS Genet. Jul 2012; 8(7): e1002786). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 06, 2020

Variant summary: BRIP1 c.3411_3420del10 (p.Tyr1137X) results in a premature termination codon, predicted to cause a truncation of the encoded protein but not expected to result in nonsense mediated decay. The variant was absent in 249576 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3411_3420del10 in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. The variant resides in a region that has been shown to affect binding of TopBP1 a protein that plays an important role in the control of DNA replication checkpoint (PMID: 20159562). However, functional significance of this interaction is limited. One ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS- possibly pathogenic until additional clinical and functional evidence is obtained. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 03, 2022

This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 232964). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This sequence change creates a premature translational stop signal (p.Tyr1137*) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 113 amino acid(s) of the BRIP1 protein. -

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: rs876660100; hg19: chr17-59760986;