rs747604569

chr17-61849152-G-Achr17-61849152-G-Cchr17-61849152-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1PP3PP5_Very_Strong

The NM_032043.3(BRIP1):c.484C>T(p.Arg162Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R162R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 3.42

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-61849152-G-A is Pathogenic according to our data. Variant chr17-61849152-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.484C>T	p.Arg162Ter	stop_gained	5/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.484C>T	p.Arg162Ter	stop_gained	5/20	1	NM_032043.3	P2	Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251320

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461266

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726980

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151994

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000176

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 31, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 20, 2023	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 28, 2021	This variant changes 1 nucleotide in exon 5 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with ovarian cancer, melanoma, and Lynch syndrome–associated cancer and/or polyps (PMID: 25980754, 31745173, 32756499). This variant has also been identified in 2/251320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 02, 2022	The p.R162* pathogenic mutation (also known as c.484C>T), located in coding exon 4 of the BRIP1 gene, results from a C to T substitution at nucleotide position 484. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

This sequence change creates a premature translational stop signal (p.Arg162*) in the BRIP1 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs747604569, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 186411). Studies have shown that this premature translational stop signal results in skipping of exon 5 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

BRIP1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2024

The BRIP1 c.484C>T variant is predicted to result in premature protein termination (p.Arg162*). This variant has been reported in individual(s) with personal history of Lynch syndrome or colorectal cancer (for example, Supplemental Table 1, Yurgelun et al. 2015. PubMed ID: 25980754; Table S5, Akcay et al. 2020. PubMed ID: 32658311). This variant has also been reported in individual(s) with breast cancer or family history of breast cancer (for example, Table S1, Zheng et al. 2018. PubMed ID: 30130155; Table S1, Shao et al. 2019. PubMed ID: 31742824). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186411/). Nonsense variants in BRIP1 are considered pathogenic. In summary, this variant is interpreted as pathogenic. -

Fanconi anemia complementation group J

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 26, 2019

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 29, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25980754, 32658311, 31214711, 31742824, 25646469, 32829589, 29922827, 32756499) -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 06, 2016

Variant summary: The BRIP1 c.484C>T (p.Arg162X) variant results in a premature termination codon, predicted to cause a truncated or absent BRIP1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.1871C>A/p.S624X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121388 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). This variant has been reported in one suspected LS patient and B cell lymphoma sample. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic, without evidence to independently evaluate. Taken together, this variant is classified as likely pathogenic until more information becomes available. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.51

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.82

MutationTaster

Benign

1.0

A;A

Vest4

0.92

GERP RS

4.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.51

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.51

Position offset: -23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over