NM_032043.3:c.1_2delAT

Variant names:

• chr17-61861537-CAT-C
• rs876661246
• NM_032043.3:c.1_2delAT

Variant summary

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

The NM_032043.3(BRIP1):​c.1_2delAT​(p.Met1ValfsTer6) variant causes a frameshift, start lost change. The variant was absent in control chromosomes in GnomAD project. 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:3
• 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 10 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 23 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.1_2delAT	p.Met1ValfsTer6	frameshift_variant, start_lost	Exon 2 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.1_2delAT	p.Met1ValfsTer6	frameshift_variant, start_lost	Exon 2 of 20	1	NM_032043.3	ENSP00000259008.2

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:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Feb 11, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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." -

Jul 12, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRIP1 c.1_2del variant disrupts the translation initiation codon of the BRIP1 mRNA and is predicted to interfere with BRIP1 protein synthesis. However, there are downstream alternate initiation codons that may rescue translation initiation. In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 30322717 (2018), 31341520 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, we are unable to determine the clinical significance of this variant. -

Breast and/or ovarian cancer Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Apr 06, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;