17-61847151-C-T

Position:

• chr17-61847151-C-T

Variant summary

Our verdict is Benign. Variant got -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 128192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61847151-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.577G>A	p.Val193Ile	missense_variant	6/20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.577G>A	p.Val193Ile	missense_variant	6/20	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

GnomAD3 exomes AF: 0.00370 AC: 931 AN: 251342 Hom.: 8 AF XY: 0.00379 AC XY: 515 AN XY: 135844

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 SAS exome AF: 0.00225

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

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.00369

Gnomad4 ASJ exome AF: 0.00505

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00255

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.00451

Gnomad4 OTH exome AF: 0.00411

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

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.00490

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00471 Hom.: 10

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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 07, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BRIP1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:7 Other:1

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 09, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 09, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	May 30, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 04, 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 15, 2015	- -

Familial cancer of breast Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 02, 2023	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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

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	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 23, 2021	- -

Fanconi anemia complementation group J Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	May 25, 2016	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 01, 2023

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

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

May 25, 2016

- -

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
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.010
gMVP		0.14

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: rs4988346; hg19: chr17-59924512;