rs587781388

chr17-61857172-CACA-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_032043.3(BRIP1):c.262_264del(p.Cys88del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000124 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. C88C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: BRIP1 NM_032043.3 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 5.04

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 Uncertain_significance. Variant got 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_032043.3. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.262_264del	p.Cys88del	inframe_deletion	4/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.262_264del	p.Cys88del	inframe_deletion	4/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251452 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135900

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461602 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 727108

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 13, 2019	Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 27, 2022	The frequency of this variant in the general population, 0.00002 (5/251452 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with pancreatic cancer (PMID: 28767289 (2017) and breast cancer (PMID: 26976419 (2016)). The variant has also been reported in an unaffected individual (PMID: 31214711 (2020)). Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 25, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2023	In-frame deletion of one amino acid in a non-repeat region; Observed in individuals with breast and pancreatic cancer (Tung et al., 2016; Shindo et al., 2017; Hu et al., 2020); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26976419, 28767289, 31214711, 32659497) -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 30, 2023	The c.262_264delTGT variant (also known as p.C88del) is located in coding exon 3 of the BRIP1 gene. This variant results from an in-frame TGT deletion at nucleotide positions 262 to 264. This results in the in-frame deletion of a cysteine at codon 88. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J Clin Oncol, 2016 May;34:1460-8). This alteration was also identified in a cohort of patients with pancreatic cancer or other periampullary neoplasms tested for hereditary cancer risk via a multi-gene panel (Shindo K et al. J Clin Oncol, 2017 Oct;35:3382-3390). This alteration has been reported with a carrier frequency of 0.00026 in 7636 unselected prostate cancer patients and 0.00008 in 12366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2012	There is insufficient or conflicting evidence for classification of this alteration. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 11, 2023	This variant causes an in-frame deletion of one amino acid (codon 88) in the BRIP1 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419), two individuals affected with pancreatic cancer (PMID: 28767289) and two individuals affected with prostate cancer (PMID: 31214711). This variant has been identified in 5/251452 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in a control individual (PMID: 31214711). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 05, 2022

This variant, c.262_264del, results in the deletion of 1 amino acid(s) of the BRIP1 protein (p.Cys88del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587781388, gnomAD 0.01%). This variant has been observed in individual(s) with breast cancer, pancreatic cancer, and prostate cancer (PMID: 26976419, 28767289, 31214711). ClinVar contains an entry for this variant (Variation ID: 140945). 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. -

BRIP1-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2023

The BRIP1 c.262_264delTGT variant is predicted to result in an in-frame deletion (p.Cys88del). This variant has been reported in at least three individuals with different types of cancer (pancreatic ductal adenocarcinoma, Shindo et al. 2017. PubMed ID: 28767289; breast cancer, Tung et al. 2016. PubMed ID: 26976419; prostate cancer, search rs587781388 in Table S6, Momozawa et al. 2020. PubMed ID: 31214711). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is classified as a variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/140945/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRIP1 p.Cys88del variant was identified in 1 of 976 proband chromosomes (frequency: 0.001) from individuals or families with stage I to III breast cancer (Tung 2016). The variant was also identified in the following databases: dbSNP (ID: rs587781388) as “With Uncertain significance allele”, ClinVar (6x as uncertain significance by Ambry Genetics, GeneDx, Invitae, Color Genomics, Laboratory Corporation of America), and Cosmic (reported 1x as confirmed somatic Carcinoma in Endometrium). The variant was not identified in MutDB, or the Zhejiang University Database. The variant was identified in control databases in 5 of 246232 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 15304 chromosomes (freq: 0.00013), South Asian in 1 of 30782 chromosomes (freq: 0.000032), European (Non-Finnish) in 2 of 111694 chromosomes (freq: 0.000018); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, Latino, and other populations. The c.262_264del variant is an in-frame deletion resulting in the removal of a cysteine (cys) residue at codon 88; the impact of this alteration on BRIP1 protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Oct 05, 2022

The BRIP1 c.262_264del (p.Cys88del) change has a maximum subpopulation frequency 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The change results in the deletion of a single cysteine residue in a region without a known function at the N-terminal end of the BRIP1 gene. This variant has been reported in an individual with breast cancer (PMID: 26976419), as well as in individuals affected with pancreatic cancer and prostate cancer (PMID: 28767289, 31214711). To our knowledge, this variant has not been reported in individuals with ovarian cancer or Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as 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: rs587781388; hg19: chr17-59934533;