rs587780247

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_032043.3(BRIP1):c.316C>T(p.Arg106Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:4

Conservation

PhyloP100: 2.04

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05186683).

BP6

Variant 17-61857121-G-A is Benign according to our data. Variant chr17-61857121-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128184.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=12}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.316C>T	p.Arg106Cys	missense_variant	4/20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.316C>T	p.Arg106Cys	missense_variant	4/20	1	NM_032043.3	ENSP00000259008	P2	Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

251452

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

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:

0.000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000664

AC:

AN:

1461730

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000719

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia complementation group J

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 06, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 15, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 23, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Familial cancer of breast

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 02, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 20, 2022	The p.R106C variant (also known as c.316C>T), located in coding exon 3 of the BRIP1 gene, results from a C to T substitution at nucleotide position 316. The arginine at codon 106 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was observed within 1 of 13213 individuals with a personal history of breast cancer and 1/5242 controls (Easton DF et al. J Med Genet, 2016 05;53:298-309). It was also reported in a family in which the variant was present in two siblings affected with breast cancer and absent from two cancer-free siblings (Grasel RS et al. Front Oncol, 2020 Oct;10:571330). This variant has been reported in a familial prostate cancer kindred and in one individual with colorectal cancer diagnosed under age 50 (Ray AM et al. Br. J. Cancer. 2009 Dec;101:2043-7; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 19, 2016	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 22, 2021	- -

Ovarian neoplasm

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Nov 22, 2019	This variant has been identified in individuals with breast, colon and prostate cancer (Ray 2009, Easton 2016, Pearlman 2017), but has not to our knowledge been reported in an individual with ovarian cancer. The majority of pathogenic variants reported in the BRIP1 gene to date are truncating variants. This variant has an overall allele frequency of 0.0001 in the Broad Institute ExAC Browser (http://exac.broadinstitute.org/). In silico analyses indicate that this variant may not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 06, 2016	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 02, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, melanoma, prostate cancer, or colon cancer, but also in unaffected controls (PMID: 19935797, 26921362, 27978560, 33134171, 35264596); This variant is associated with the following publications: (PMID: 19935797, 27978560, 26921362, 28492532, 26689913, 33134171, 32522261, 35264596) -

BRIP1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 14, 2022

The BRIP1 c.316C>T variant is predicted to result in the amino acid substitution p.Arg106Cys. This variant was reported in individuals with prostate cancer, lung adenocarcinoma, or colon cancer (Table 3, Ray et al. 2009. PubMed ID: 19935797; Supplementary data set 12, Lu et al. 2015. PubMed ID: 26689913; eTable 2, Pearlman et al. 2017. PubMed ID: 27978560). This variant was also reported as uncertain in a cohort study of hereditary cancer testing (Table S1, Velázquez. 2020. PubMed ID: 32522261). In a case control study, this variant was identified in one individual with breast cancer and found in one unaffected individual (Table S1, Easton et al. 2016. PubMed ID: 26921362). In addition, a different variant affecting the same amino acid (p.Arg106His) was reported in individuals with rectum cancer/pancreatic adenocarcinoma (eTable 2, Pearlman et al. 2017. PubMed ID: 27978560; Shindo. 2017. PubMed ID: 28767289). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-59934482-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/128184/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Sep 19, 2017

Variant summary: The BRIP1 c.316C>T (p.Arg106Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant was found in the control population dataset of gnomAD in 32/287682 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.000203 (7/34416). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. The variant has been reported in affected individuals in the literature, without strong evidence for causality (Ray_2009, Easton_2016, Pearlman_2016). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, based on the relatively high allele frequency of the variant in the control population, this variant is classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.080

T;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.46

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.052

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

N;N

MutationTaster

Benign

0.99

N;N

PrimateAI

Benign

0.19

PROVEAN

Benign

-0.36

N;.

REVEL

Benign

0.067

Sift

Benign

0.18

T;.

Sift4G

Benign

0.086

T;T

Polyphen

0.0

B;.

Vest4

0.11

MVP

0.53

MPC

0.22

ClinPred

0.055

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.039

gMVP

0.24

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

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