rs876661246

chr17-61861537-CAT-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PS1_Moderate PP5

The NM_032043.3(BRIP1):c.1_2del(p.Met1?) variant causes a frameshift, start lost change. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRIP1 NM_032043.3 frameshift, start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 4.55

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 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 428 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_032043.3 (BRIP1) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 187378
• PP5: Variant 17-61861537-CAT-C is Pathogenic according to our data. Variant chr17-61861537-CAT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234832.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	UniProt
BRIP1	NM_032043.3	c.1_2del	p.Met1?	frameshift_variant, start_lost	2/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.1_2del	p.Met1?	frameshift_variant, start_lost	2/20	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 2016

This deletion of two nucleotides is denoted BRIP1 c.1_2delAT at the cDNA level and alters the initiator Methionine codon. The resultant protein would be described as p.Met1?" to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. Although BRIP1 c.1_2delAT has not, to our knowledge, been previously published as pathogenic or benign, it is predicted to alter normal protein production. Based on the currently available evidence, we consider BRIP1 c.1_2delAT to be a likely pathogenic variant." -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 06, 2021

This sequence change deletes 2 nucleotides from exon 2 of the BRIP1 mRNA (c.1_2delAT), affecting the initiator methionine. While it is expected to result in an absent or disrupted protein product, alternate in-frame methionines at codons 4, 28, or 29, located downstream of the initiator codon could potentially rescue the translation initiation. However, functional studies have not been done to test whether these alternate methionines are utilized. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with ovarian tumor (PMID:30322717). ClinVar contains an entry for this variant (Variation ID: 234832). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.1_2delAT variant, located in coding exon 1 of the BRIP1 gene, results from a deletion of two nucleotides at nucleotide positions 1 to 2, causing a translational frameshift with a predicted alternate stop codon (p.M1?). Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there are in-frame methionines at 3 and 27 amino acids from the initiation site, which may result in N-terminal truncation of unknown functional significance. This alteration has been reported in women diagnosed with ovarian cancer (Arvai KJ et al. Hered Cancer Clin Pract. 2019 Jul;17:19; Lhotova K et al. Cancers (Basel) 2020 Apr;12:). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs876661246; hg19: chr17-59938898;