rs587781388

Variant names:

• chr17-61857172-CACA-C
• rs587781388
• NM_032043.3:c.262_264delTGT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_032043.3(BRIP1):​c.262_264delTGT​(p.Cys88del) variant causes a conservative 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 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 5.04
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• familial ovarian cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• Fanconi anemia complementation group J

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary breast carcinoma

  Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.262_264delTGT	p.Cys88del	conservative_inframe_deletion	Exon 4 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.262_264delTGT	p.Cys88del	conservative_inframe_deletion	Exon 4 of 20	1	NM_032043.3	ENSP00000259008.2

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

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251452 AF XY: 0.0000221

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 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

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111746

Other (OTH) AF: 0.00 AC: 0 AN: 60396

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

African (AFR) AF: 0.0000483 AC: 2 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

May 10, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRIP1 c.262_264del (p.Cys88del) variant has been reported in the published literature in individuals with pancreatic cancer (PMID: 28767289 (2017)) and breast cancer (PMID: 26976419 (2016)). The variant has also been reported in reportedly healthy individuals (PMIDs: 31214711 (2020) and 36243179 (2022)). The frequency of this variant in the general population, 0.00002 (5/251452 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

May 09, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Aug 13, 2019

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. -

Hereditary cancer-predisposing syndrome Uncertain:3

Jan 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 20, 2012

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

There is insufficient or conflicting evidence for classification of this alteration. -

Jul 11, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Uncertain:2

Oct 05, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 11, 2018

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

May 24, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRIP1 c.262_264delTGT (p.Cys88del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 251452 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.262_264delTGT has been reported in the literature in individuals affected with pancreatic cancer, breast cancer or prostate cancer, as well as in controls (Shindo_2017, Tung_2016, Momozawa_2020, Okawa_2023). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28767289, 26976419, 36243179, 31214711). ClinVar contains an entry for this variant (Variation ID: 140945). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 disorder Uncertain:1

Dec 21, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs587781388; hg19: chr17-59934533; COSMIC: COSV51995747; COSMIC: COSV51995747;