17-61743106-A-G

Position:

• chr17-61743106-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_032043.3(BRIP1):​c.2286T>C​(p.Arg762=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,614,018 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: BRIP1 NM_032043.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 2.51

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 17-61743106-A-G is Benign according to our data. Variant chr17-61743106-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0016 (243/152318) while in subpopulation AFR AF= 0.00496 (206/41572). AF 95% confidence interval is 0.0044. There are 1 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.2286T>C	p.Arg762=	synonymous_variant	16/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.2286T>C	p.Arg762=	synonymous_variant	16/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152200 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.000545 AC: 137 AN: 251252 Hom.: 1 AF XY: 0.000471 AC XY: 64 AN XY: 135784

Gnomad AFR exome AF: 0.00541

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000254 AC: 371 AN: 1461700 Hom.: 1 Cov.: 31 AF XY: 0.000226 AC XY: 164 AN XY: 727142

Gnomad4 AFR exome AF: 0.00600

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000872

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.00160 AC: 243 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74462

Gnomad4 AFR AF: 0.00496

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000723 Hom.: 0

Bravo AF: 0.00203

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	BRIP1: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2016	Variant summary: The BRIP1 c.2286T>C variant affects a conserved nucleotide, resulting in no amino acid change. One in-silico tool predicts a damaging outcome for this variant. 3/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect ESE site of SF2/ASF (IgM-BRCA1). However, these predictions have not been confirmed by experimental studies. This variant is found in 61/121286 control chromosomes (1 homozygote) at a frequency of 0.0005029, which is about 8 times the maximal expected frequency of a pathogenic BRIP1 allele (0.0000625), suggesting this variant is benign. In addition, multiple clinical laboratories classified this variant as likely benign/benign. Taken together, this variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 31, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 16, 2022	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 25, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 23, 2014	This alteration is classified as likely 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. -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 11, 2017	- -

Fanconi anemia complementation group J Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 06, 2016	- -
Likely 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 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

May 01, 2023

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRIP1 p.Arg762= variant was identified in 1 of 188 proband chromosomes (frequency: 0.005) from individuals or families with prostate cancer (Ray 2009). The variant was also identified in the following databases, dbSNP (ID: rs61754141) as “With Uncertain significance allele”, ClinVar (7x, as benign by GeneDx, Invitae, as likely benign by Ambry Genetics, Counsyl, as uncertain significance by Illumina), Clinvitae (6x, with conflicting predictions as benign, likely benign and uncertain significance), Zhejiang Colon Cancer Database (1x with unknown pathogenicity). The variant was not identified in Cosmic, MutDB, databases. The variant was identified in control databases in 179 of 276976 (1 homozygous) chromosomes at a frequency of 0.0006 in the following populations: African in 129 of 24038 (1 homozygous) chromosomes (freq. 0.005), other in 2 of 6462 chromosomes (freq. 0.0003), Latino in 25 of 34400 chromosomes (freq. 0.0007), European in 22 of 126538 chromosomes (freq. 0.0002), and South Asian in 1 of 30782 chromosomes (freq. 0.00003), increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). The p.Arg762Arg variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Mar 01, 2023

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Ovarian neoplasm Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Sep 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.3
DANN	Benign	0.70

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: rs61754141; hg19: chr17-59820467;