rs28997569

Variant names:

• chr17-61808595-G-A
• rs28997569
• NM_032043.3:c.790C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-61808595-G-A
• chr17-61808595-G-C
• chr17-61808595-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_032043.3(BRIP1):​c.790C>T​(p.Arg264Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,613,856 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:19 O:1
• Conservation: PhyloP100: 3.66
• Publications: 26 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041837633).
• BP6: Variant 17-61808595-G-A is Benign according to our data. Variant chr17-61808595-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128195.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.790C>T	p.Arg264Trp	missense_variant	Exon 7 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.790C>T	p.Arg264Trp	missense_variant	Exon 7 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.00100 AC: 152 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000846

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000828 AC: 208 AN: 251076 AF XY: 0.000877

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00118 AC: 1719 AN: 1461734 Hom.: 3 Cov.: 31 AF XY: 0.00117 AC XY: 853 AN XY: 727172

African (AFR) AF: 0.000478 AC: 16 AN: 33478

American (AMR) AF: 0.000514 AC: 23 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86254

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53418

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00134 AC: 1490 AN: 1111880

Other (OTH) AF: 0.00124 AC: 75 AN: 60392

GnomAD4 genome AF: 0.000999 AC: 152 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74390

African (AFR) AF: 0.000844 AC: 35 AN: 41486

American (AMR) AF: 0.000785 AC: 12 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 67990

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00101

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000708 AC: 86

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:19 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Jan 08, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 22, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.790C>T, located in exon 6 of the BRIP1, is predicted to result in the substitution of arginine by tryptophan at codon 264, p.(Arg264Trp). This variant is found in 130/117794, with a filter allele frequency of 0.089% at 99% confidence in the gnomAD v2.1.1 database (European non-Finnish non-cancer data set). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.338) is indeterminate regarding the effect that it may have on protein function according Pejaver 2022 thresholds (PMID: 36413997). This variant has been reported in the ClinVar database (2x benign, 17x likely benign, 3x uncertain significance) and in the LOVD database (6x likely benign, 1x uncertain significance, 2x not classified). Based on currently available information, the variant c.790C>T is classified as an uncertain significance variant according to ACMG guidelines. -

Dec 07, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial cancer of breast Uncertain:1 Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Mar 28, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The BRIP1 variant designated as NM_032043.2:c.790C>T (p.Arg264Trp) is now classified as likely benign. The variant is present in approximately 1 in 500 individuals in European and African populations (exac.broadinstitute.org). This population frequency is not consistent with a high-risk cancer variant. In addition, there are no reports of pathogenic missense variants in this BRIP1 protein domain. This variant has been classified as likely benign by other laboratories (ClinVar Variation ID: 128195). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BRIP1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

not specified Uncertain:1 Benign:2 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Aug 02, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 08, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRIP1: BP1 -

Feb 23, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group J Uncertain:1 Benign:1

Jul 18, 2016

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Malignant tumor of breast Benign:2

-

Center of Medical Genetics and Primary Health Care

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRIP1 p.Arg264Trp variant was identified in 55 of 46810 proband chromosomes (frequency: 0.001) from Italian, American, British and Colombian individuals or families with a wide spectrum of cancers (in population based studies, unselected for family history): BRCA1/2 negative, male/female breast cancer, prostate cancer, ovarian cancer, Lynch syndrome associated cancer and/or polyps, CRC, pancreatic cancer, hereditary prostate cancer and Fanconi anemia; and was present in 44 of 29724 control chromosomes (frequency: 0.001) from healthy individuals (Silvestri_2011_21165771, Bodian_2014_24728327, Hu_2016_26483394, Yurgelun_2015_25980754, Tung_20016_26976419, Seal_2006_17033622, Easton_2016_26921362, Levitus_2005_16116423, Pearlman_2016_27978560, Ramus_2015_26315354, Cock-Rada_2017_28528518, Ray_2009_19935797). In one prostate cancer family, the variant was identified in two out of three cases and was not present in the unaffected brother of the proband (Ray_2009_19935797). In 1 male proband with breast cancer, diagnosed at 76 yrs of age, DNA extracted from the micro-dissected breast tumor sample showed that no loss of the wild-type allele had occurred in tumor cells (Silvestri_2011_21165771). The variant was identified in dbSNP (ID: rs28997569) “With Likely benign allele”, ClinVar (classified likely benign by Invitae, Ambry Genetics, Genetic Services Laboratory (University of Washington), Counsyl, Color Genomics Inc, Quest Diagnostics Nichols Institute San Juan Capistrano, and GeneDx, and classification not provided by ITMI), Clinvitae (5x) and Zhejiang Colon Cancer Database, and was not identified in Cosmic or MutDB. The variant was also identified in control databases in 229 of 276746 chromosomes at a frequency of 0.0008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 17 of 24030 chromosomes (freq: 0.0007), “Other” in 11 of 6452 chromosomes (freq: 0.002), Latino in 15 of 34408 chromosomes (freq: 0.0004), European Non-Finnish in 145 of 126288 chromosomes (freq: 0.001), Ashkenazi Jewish in 28 of 10142 chromosomes (freq: 0.003), European Finnish in 7 of 25786 chromosomes (freq: 0.0003), and South Asian in 6 of 30782 chromosomes (freq: 0.0002); it was not observed in the East Asian population. The p.Arg264 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Breast and/or ovarian cancer Benign:1

Jun 21, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRIP1-related disorder Benign:1

Mar 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ovarian cancer Benign:1

Jul 18, 2016

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.042	T;T
MetaSVM	Uncertain	-0.0027	T
MutationAssessor	Pathogenic	3.1	M;M
PhyloP100		3.7
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.55
MVP		0.96
MPC		0.67
ClinPred		0.032	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.72
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs28997569; hg19: chr17-59885956; COSMIC: COSV52000602;