rs781556845

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_032043.3(BRIP1):c.2567A>G(p.Tyr856Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,612,758 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y856H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 5.12

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_032043.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3 link	c.2567A>G	p.Tyr856Cys	missense_variant	Exon 18 of 20	ENST00000259008.7	NP_114432.2	Q9BX63-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 link	c.2567A>G	p.Tyr856Cys	missense_variant	Exon 18 of 20	1	NM_032043.3	ENSP00000259008.2		Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251304

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460614

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726680

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

AC:

AN:

33448

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44722

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26112

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39646

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86236

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53406

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1110934

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60348

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000724

AC:

0.0000724008

AN:

0.0000724008

Gnomad4 AMR

AF:

0.0000654

AC:

0.0000654365

AN:

0.0000654365

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:2

Feb 13, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 27, 2023

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Aug 30, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Y856C variant (also known as c.2567A>G), located in coding exon 17 of the BRIP1 gene, results from an A to G substitution at nucleotide position 2567. The tyrosine at codon 856 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in 1/1824 women with triple-negative breast cancer (Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Dec 12, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ovarian cancer;C1836860:Fanconi anemia complementation group J

Uncertain:1

Apr 29, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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

Uncertain:1

Sep 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 856 of the BRIP1 protein (p.Tyr856Cys). This variant is present in population databases (rs781556845, gnomAD 0.02%). This missense change has been observed in individual(s) with triple-negative breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 418097). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BRIP1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Oct 20, 2014

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is denoted BRIP1 c.2567A>G at the cDNA level, p.Tyr856Cys (Y856C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Tyr856Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Tyr856Cys occurs at a position that is highly conserved through mammals and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRIP1 Tyr856Cys is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.7

D;.

REVEL

Pathogenic

0.76

Sift

Uncertain

0.014

D;.

Sift4G

Uncertain

0.011

D;D

Polyphen

1.0

D;.

Vest4

0.79

MVP

0.99

MPC

0.77

ClinPred

0.97

GERP RS

5.7

Varity_R

0.78

gMVP

0.66

Mutation Taster

=71/29

polymorphism

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