17-61776394-C-T

Variant names:

• chr17-61776394-C-T
• rs4988352
• NM_032043.3:c.2097+7G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_032043.3(BRIP1):​c.2097+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,613,980 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (13 hom.)
• Consequence: BRIP1 NM_032043.3 splice_region, intron
• Scores: Splicing: ADA: 0.00007669
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:26
• Conservation: PhyloP100: 0.00700

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-61776394-C-T is Benign according to our data. Variant chr17-61776394-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136147.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=8, Likely_benign=10}. Variant chr17-61776394-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00234 (357/152284) while in subpopulation NFE AF= 0.00394 (268/68034). AF 95% confidence interval is 0.00355. There are 1 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.2097+7G>A		splice_region_variant, intron_variant	Intron 14 of 19	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.2097+7G>A		splice_region_variant, intron_variant	Intron 14 of 19	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 357 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00394

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00225 AC: 566 AN: 251276 Hom.: 2 AF XY: 0.00214 AC XY: 290 AN XY: 135812

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00393

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00298 AC: 4360 AN: 1461696 Hom.: 13 Cov.: 30 AF XY: 0.00284 AC XY: 2064 AN XY: 727150

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00195

Gnomad4 NFE exome AF: 0.00360

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00234 AC: 357 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.00205 AC XY: 153 AN XY: 74462

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.00394

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00300 Hom.: 1

Bravo AF: 0.00234

EpiCase AF: 0.00344

EpiControl AF: 0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:26

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:9

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 02, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 30, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2024	BRIP1: BP4, BS2 -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2013	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. -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 23, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 19, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 18, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jun 18, 2018	- -

Familial cancer of breast Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 01, 2023	This variant is considered benign. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 19, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Fanconi anemia complementation group J Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 25, 2023

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2025

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRIP1 c.2097+7G>A variant was identified in 3 of 436 proband chromosomes (frequency: 0.007) from individuals or families with breast or ovarian cancer and was identified in 1 of 146 control chromosomes (frequency: 0.005) from healthy individuals (Guenard_2008, Rutter_2003, Vahteristo_2006). The variant was also identified in dbSNP (ID: rs4988352) “With Uncertain significance allele”, ClinVar (classified benign by Invitae, GeneDx, likely benign by Counsyl, Quest Diagnostics Nichols Institute San Juan Capistrano and Color Genomics Inc, and uncertain significance by Illumina), Clinvitae (6x), Zhejiang Colon Cancer Database (7x), and was not identified in Cosmic or MutDB. The variant was identified in control databases in 644 of 277018 chromosomes (2 homozygous) at a frequency of 0.002 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 8 of 24028 chromosomes (freq: 0.0003), Other in 10 of 6462 chromosomes (freq: 0.002), Latino in 72 of 34396 chromosomes (freq: 0.002), European Non-Finnish in 518 (1 homozygous) of 126558 chromosomes (freq: 0.004), European Finnish in 34 (1 homozygous) of 25788 chromosomes (freq: 0.001), and South Asian in 2 of 30780 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish and East Asian populations. 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 this variant meets our laboratory's criteria to be classified as benign. -

Ovarian neoplasm Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Jun 03, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.2
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000077
dbscSNV1_RF	Benign	0.0020
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: rs4988352; hg19: chr17-59853755;