17-61847151-C-T

Variant names:

• chr17-61847151-C-T
• rs4988346
• NM_032043.3:c.577G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032043.3(BRIP1):​c.577G>A​(p.Val193Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,613,630 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (33 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:30 O:1
• Conservation: PhyloP100: -0.580
• Publications: 36 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005566299).
• BP6: Variant 17-61847151-C-T is Benign according to our data. Variant chr17-61847151-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00305 (464/152290) while in subpopulation NFE AF = 0.0049 (333/68026). AF 95% confidence interval is 0.00446. There are 2 homozygotes in GnomAd4. There are 216 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.577G>A	p.Val193Ile	missense_variant	Exon 6 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.577G>A	p.Val193Ile	missense_variant	Exon 6 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 466 AN: 152172 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00489

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00370 AC: 931 AN: 251342 AF XY: 0.00379

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00536

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00405 AC: 5912 AN: 1461340 Hom.: 33 Cov.: 31 AF XY: 0.00404 AC XY: 2936 AN XY: 727010

African (AFR) AF: 0.000628 AC: 21 AN: 33454

American (AMR) AF: 0.00369 AC: 165 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00505 AC: 132 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00255 AC: 220 AN: 86254

European-Finnish (FIN) AF: 0.00114 AC: 61 AN: 53404

Middle Eastern (MID) AF: 0.00937 AC: 54 AN: 5760

European-Non Finnish (NFE) AF: 0.00451 AC: 5011 AN: 1111608

Other (OTH) AF: 0.00411 AC: 248 AN: 60370

GnomAD4 genome AF: 0.00305 AC: 464 AN: 152290 Hom.: 2 Cov.: 32 AF XY: 0.00290 AC XY: 216 AN XY: 74470

African (AFR) AF: 0.000746 AC: 31 AN: 41550

American (AMR) AF: 0.00307 AC: 47 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.000943 AC: 10 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00490 AC: 333 AN: 68026

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00450 Hom.: 12

Bravo AF: 0.00340

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00396 AC: 481

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00643

EpiControl AF: 0.00806

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:30 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:8

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

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

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRIP1: BP4, BS2 -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:7 Other:1

May 14, 2017

GeneDx

Significance: 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. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2019

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 09, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Aug 04, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Oct 09, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 30, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Benign:3

Mar 02, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: 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

- -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group J Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

May 25, 2016

Counsyl

Significance: 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. -

Breast and/or ovarian cancer Benign:1

May 01, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ovarian cancer Benign:1

May 25, 2016

Counsyl

Significance: 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. -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRIP1 p.Val193Ile variant was identified in 4 of 726 proband chromosomes (frequency: 0.006) from individuals with breast and prostate cancer and was present in 14 of 4556 control chromosomes (frequency: 0.003) from healthy individuals (Kote-Jarai 2009,Rutter 2003, Vahteristo 2006, Wong 2011). The variant was identified in dbSNP (rs4988346) as “with benign allele”, ClinVar (interpreted as "benign" by Invitae and 8 others and "likely benign" by True Health Diagnostics). The variant was identified in control databases in 986 of 277,084 chromosomes (9 homozygous) at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 13 of 24,026 chromosomes (freq: 0.0005), Other in 39 of 6462 chromosomes (freq: 0.006), Latino in 135 of 34,414 chromosomes (freq: 0.004), European in 650 of 126,616 chromosomes (freq: 0.005), Ashkenazi Jewish in 54 of 10,148 chromosomes (freq: 0.005), Finnish in 27 of 25,780 chromosomes (freq: 0.001), and South Asian in 68 of 30,782 chromosomes (freq: 0.002). The variant was not observed in the East Asian population. The p.Val193 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.028
DANN	Benign	0.54
DEOGEN2	Benign	0.093	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0096	N
LIST_S2	Benign	0.40	T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		-0.58
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.26	N;.
REVEL	Benign	0.071
Sift	Benign	0.91	T;.
Sift4G	Benign	0.61	T;T
Polyphen		0.0	B;.
Vest4		0.035
MVP		0.29
MPC		0.13
ClinPred		0.0013	T
GERP RS		-8.2
PromoterAI		0.0035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.010
gMVP		0.14
Mutation Taster		=100/0	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: rs4988346; hg19: chr17-59924512;