17-61686104-T-C

Position:

• chr17-61686104-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032043.3(BRIP1):​c.2637A>G​(p.Glu879=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 1,613,482 control chromosomes in the GnomAD database, including 386,600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (43212 hom., cov: 31)
  • Exomes 𝑓: 0.68 (343388 hom.)
• Consequence: BRIP1 NM_032043.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -0.191

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 17-61686104-T-C is Benign according to our data. Variant chr17-61686104-T-C is described in ClinVar as [Benign]. Clinvar id is 183703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61686104-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.191 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.2637A>G	p.Glu879=	synonymous_variant	19/20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.2637A>G	p.Glu879=	synonymous_variant	19/20	1	NM_032043.3	ENSP00000259008	P2

Frequencies

GnomAD3 genomes AF: 0.742 AC: 112750 AN: 151928 Hom.: 43144 Cov.: 31

Gnomad AFR AF: 0.904

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.831

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.893

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.656

Gnomad OTH AF: 0.762

GnomAD3 exomes AF: 0.718 AC: 180347 AN: 251210 Hom.: 66500 AF XY: 0.708 AC XY: 96185 AN XY: 135814

Gnomad AFR exome AF: 0.911

Gnomad AMR exome AF: 0.867

Gnomad ASJ exome AF: 0.696

Gnomad EAS exome AF: 0.891

Gnomad SAS exome AF: 0.699

Gnomad FIN exome AF: 0.509

Gnomad NFE exome AF: 0.663

Gnomad OTH exome AF: 0.727

GnomAD4 exome AF: 0.681 AC: 995610 AN: 1461436 Hom.: 343388 Cov.: 57 AF XY: 0.681 AC XY: 495081 AN XY: 727042

Gnomad4 AFR exome AF: 0.914

Gnomad4 AMR exome AF: 0.861

Gnomad4 ASJ exome AF: 0.694

Gnomad4 EAS exome AF: 0.893

Gnomad4 SAS exome AF: 0.702

Gnomad4 FIN exome AF: 0.519

Gnomad4 NFE exome AF: 0.664

Gnomad4 OTH exome AF: 0.702

GnomAD4 genome AF: 0.742 AC: 112888 AN: 152046 Hom.: 43212 Cov.: 31 AF XY: 0.740 AC XY: 54992 AN XY: 74298

Gnomad4 AFR AF: 0.904

Gnomad4 AMR AF: 0.831

Gnomad4 ASJ AF: 0.702

Gnomad4 EAS AF: 0.893

Gnomad4 SAS AF: 0.719

Gnomad4 FIN AF: 0.496

Gnomad4 NFE AF: 0.657

Gnomad4 OTH AF: 0.764

Alfa AF: 0.692 Hom.: 45456

Bravo AF: 0.776

Asia WGS AF: 0.788 AC: 2743 AN: 3478

EpiCase AF: 0.678

EpiControl AF: 0.684

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
Benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 13, 2019	Curator: Arleen D. Auerbach. Submitters to LOVD: Maximiliano Zeballos, Yukihide Momozawa. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 23, 2022	- -

Fanconi anemia complementation group J Benign:2

Benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Familial cancer of breast Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 28, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 07, 2014	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. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 19, 2022

- -

Ovarian neoplasm Benign:1

Benign, criteria provided, single submitter

clinical testing

Counsyl

Jun 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.2
DANN	Benign	0.62

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: rs4986765; hg19: chr17-59763465;