rs587780224

Positions:

• chr17-61801265-TTG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_032043.3(BRIP1):​c.1126_1127del​(p.Gln376AsnfsTer18) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,459,774 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRIP1 NM_032043.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.81

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-61801265-TTG-T is Pathogenic according to our data. Variant chr17-61801265-TTG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128151.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.1126_1127del	p.Gln376AsnfsTer18	frameshift_variant	8/20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.1126_1127del	p.Gln376AsnfsTer18	frameshift_variant	8/20	1	NM_032043.3	ENSP00000259008	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251298 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135804

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459774 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726352

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 02, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

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 01, 2023

This sequence change creates a premature translational stop signal (p.Gln376Asnfs*18) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is present in population databases (rs587780224, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 128151). For these reasons, this variant has been classified as Pathogenic. -

Fanconi anemia complementation group J Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 13, 2019

- -

Ovarian neoplasm;C1836860:Fanconi anemia complementation group J Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Sep 19, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2014

This pathogenic variant is denoted BRIP1 c.1126_1127delCA at the cDNA level and p.Gln376AsnfsX18 (Q376NfsX18) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TGCA[delCA]AAAT. The deletion causes a frameshift, which changes a Glutamine to an Asparagine at codon 376, and creates a premature stop codon at position 18 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not been previously reported to our knowledge, it is considered pathogenic. BRIP1 has been only recently described in association with cancer predisposition and the risks are not well understood. In one case-control study, BRIP1 truncating mutations were identified in 9/1,212 cases with breast cancer from BRCA1/2-negative families, and in 2/2,081 controls, The relative risk of breast cancer was estimated to be 2.0, resulting in lifetime risk of approximately 25% (Seal 2006). Of note, BRIP1 missense variants in this study were not associated with cancer risk. Another study found that a frameshift BRIP1 variant in the Icelandic population was associated with an 8-fold increased risk of ovarian cancer which translates to a lifetime risk of approximately 11% (Rafnar 2011). Walsh et al. (2011) also identified BRIP1 mutations in 4/360 patients with ovarian cancer, peritoneal cancer, or fallopian tube cancer unselected for family history.Fanconi Anemia (FA) is a rare autosomal recessive condition that can be caused by two mutations (one in each copy of the gene) mutations in the BRIP1 gene (Seal 2006). This condition is characterized physical abnormalities, bone marrow failure, an increased risk for malignancy in children including leukemia and certain solid tumors. The Fanconi Anemia phenotype due to BRIP1 mutations is thought to result in a lower rate of childhood solid tumors compared to the phenotype due to two BRCA2 variants (Apostolou 2013). If a BRIP1 mutation carrier'spartner also carries a BRIP1mutation, the risk to have a child with FA is 25% with each pregnancy. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2021

The c.1126_1127delCA pathogenic mutation, located in coding exon 7 of the BRIP1 gene, results from a deletion of two nucleotides at nucleotide positions 1126 to 1127, causing a translational frameshift with a predicted alternate stop codon (p.Q376Nfs*18). This variant has been identified in more than one patient with a personal and family history of breast and/or ovarian cancer (Susswein LR et al. Genet Med, 2016 08;18:823-32; Maxwell KN et al. Am J Hum Genet, 2016 May;98:801-817). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 06, 2024

Variant summary: BRIP1 c.1126_1127delCA (p.Gln376AsnfsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251298 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1126_1127delCA has been reported in the literature in at least one individual affected with breast cancer (e.g., Susswein_2016). The following publication was ascertained in the context of this evaluation (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 128151). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587780224; hg19: chr17-59878626;