17-61685986-A-G

Variant names:

• chr17-61685986-A-G
• rs4986764
• NM_032043.3:c.2755T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032043.3(BRIP1):​c.2755T>C​(p.Ser919Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 1,613,258 control chromosomes in the GnomAD database, including 289,538 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S919A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.61 (29085 hom., cov: 31)
  • Exomes 𝑓: 0.59 (260453 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21 O:1
• Conservation: PhyloP100: 0.201
• Publications: 110 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=1.3598933E-6).
• BP6: Variant 17-61685986-A-G is Benign according to our data. Variant chr17-61685986-A-G is described in ClinVar as Benign. ClinVar VariationId is 133756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032043.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	NM_032043.3	MANE Select	c.2755T>C	p.Ser919Pro	missense	Exon 19 of 20	NP_114432.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	ENST00000259008.7	TSL:1 MANE Select	c.2755T>C	p.Ser919Pro	missense	Exon 19 of 20	ENSP00000259008.2
	BRIP1	ENST00000682453.1		c.2755T>C	p.Ser919Pro	missense	Exon 20 of 21	ENSP00000506943.1
	BRIP1	ENST00000683039.1		c.2755T>C	p.Ser919Pro	missense	Exon 20 of 21	ENSP00000508303.1

Frequencies

GnomAD3 genomes AF: 0.612 AC: 92858 AN: 151790 Hom.: 29042 Cov.: 31

Gnomad AFR AF: 0.672

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.739

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.633

GnomAD2 exomes AF: 0.602 AC: 151298 AN: 251386 AF XY: 0.588

Gnomad AFR exome AF: 0.674

Gnomad AMR exome AF: 0.799

Gnomad ASJ exome AF: 0.590

Gnomad EAS exome AF: 0.715

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.588

Gnomad OTH exome AF: 0.622

GnomAD4 exome AF: 0.593 AC: 866589 AN: 1461350 Hom.: 260453 Cov.: 57 AF XY: 0.588 AC XY: 427396 AN XY: 727012

African (AFR) AF: 0.673 AC: 22521 AN: 33472

American (AMR) AF: 0.790 AC: 35317 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 15427 AN: 26132

East Asian (EAS) AF: 0.741 AC: 29418 AN: 39682

South Asian (SAS) AF: 0.460 AC: 39632 AN: 86238

European-Finnish (FIN) AF: 0.430 AC: 22990 AN: 53418

Middle Eastern (MID) AF: 0.657 AC: 3790 AN: 5766

European-Non Finnish (NFE) AF: 0.595 AC: 661511 AN: 1111540

Other (OTH) AF: 0.596 AC: 35983 AN: 60378

GnomAD4 genome AF: 0.612 AC: 92966 AN: 151908 Hom.: 29085 Cov.: 31 AF XY: 0.606 AC XY: 45004 AN XY: 74216

African (AFR) AF: 0.672 AC: 27839 AN: 41426

American (AMR) AF: 0.739 AC: 11282 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 2101 AN: 3472

East Asian (EAS) AF: 0.721 AC: 3722 AN: 5162

South Asian (SAS) AF: 0.459 AC: 2216 AN: 4824

European-Finnish (FIN) AF: 0.408 AC: 4295 AN: 10528

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.584 AC: 39645 AN: 67918

Other (OTH) AF: 0.633 AC: 1333 AN: 2106

Alfa AF: 0.600 Hom.: 81243

Bravo AF: 0.643

TwinsUK AF: 0.588 AC: 2182

ALSPAC AF: 0.601 AC: 2316

ESP6500AA AF: 0.661 AC: 2913

ESP6500EA AF: 0.589 AC: 5065

ExAC AF: 0.597 AC: 72503

Asia WGS AF: 0.540 AC: 1879 AN: 3476

EpiCase AF: 0.597

EpiControl AF: 0.610

ClinVar

Significance: Benign

Submissions summary: Benign:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6 Other:1

Aug 13, 2019

Leiden Open Variation Database

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitters to LOVD: Maximiliano Zeballos, Yukihide Momozawa.

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Fanconi anemia complementation group J Benign:3

Jun 18, 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.

Aug 18, 2017

IntelligeneCG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23644138, 26790966, 24301948, 28382101, 24728327, 27153395, 26921362, 15113441, 23473757)

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Hereditary cancer-predisposing syndrome Benign:3

Jul 10, 2025

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 04, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 18, 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.

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.

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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ovarian cancer Benign:1

Jun 18, 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.

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.9
DANN	Benign	0.90
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0000014	T
MetaSVM	Benign	-0.94	T
PhyloP100		0.20
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.088
Sift	Benign	0.15	T
Sift4G	Benign	0.37	T
Vest4		0.061
MPC		0.20
ClinPred		0.0039	T
GERP RS		0.71
Varity_R		0.056
gMVP		0.20
Mutation Taster		=100/0	polymorphism (auto)

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: rs4986764; hg19: chr17-59763347; COSMIC: COSV51995396;