Variant rs533184563 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.590C>T	p.Ser197Phe	missense_variant	6/20	ENST00000259008.7	NP_114432.2	Q9BX63-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.590C>T	p.Ser197Phe	missense_variant	6/20	1	NM_032043.3	ENSP00000259008.2		Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

5

AN:

152174

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

7

AN:

251352

Hom.:

0

AF XY:

0.0000147

AC XY:

2

AN XY:

135852

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

58

AN:

1461460

Hom.:

0

Cov.:

31

AF XY:

0.0000426

AC XY:

31

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

5

AN:

152174

Hom.:

0

Cov.:

32

AF XY:

0.0000269

AC XY:

2

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

0

Bravo

AF:

0.0000491

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 11, 2023	In the published literature, this variant has been reported in an individual with prostate cancer (PMID: 29368341 (2018)), and in several breast cancer cases and healthy controls in a cancer risk association study (PMID: 33471991 (2021)). This variant has also been observed in the homozygous state in an individual with breast cancer (PMID: 26921362 (2016)). The frequency of this variant in the general population, 0.000054 (7/129100 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast or prostate cancer and also in unaffected controls (PMID: 26921362, 29368341, 32832836, 33471991); This variant is associated with the following publications: (PMID: 26921362, 29368341, 32832836, 33471991) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 03, 2019	The p.Ser197Phe variant in BRIP1 has been reported in 2 European individuals wit h breast cancer, once in the homozygous state and once in the heterozygous state , as well as one heterozygous individual with prostate cancer (Easton 2016, Velh o 2018). This variant has also been identified in 0.008% (2/24964) of African ch romosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. Furthermore, although the BRIP1 gene has been reported i n association with multiple cancer types, a ClinGen Expert Panel has only defini tively associated the gene to ovarian cancer and refuted its association with br east cancer. There also appears to be limited evidence for an association with p rostate cancer and no good evidence for an association with colon cancer. In sum mary, the clinical significance of the p.Ser197Phe variant is uncertain. ACMG/AM P Criteria applied: PM2_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 06, 2023	Variant summary: BRIP1 c.590C>T (p.Ser197Phe) results in a non-conservative amino acid change located in the ATP-binding domain (IPR014001) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.4e-05 in 268220 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.590C>T has been reported in the literature in individuals affected with breast cancer and prostate cancer (Easton_2016, IsaacssonVelho_2018). Large-scale meta-analyses found that BRIP1 confer high risk for familial ovarian cancer, but not for familial breast cancer (PMID: 29368626, 30733081), therefore, the reported breast cancer patients might not support a pathogenic role for the variant of interest. In addition, one of the reported breast cancer cases was described as homozygous for the variant, however no Fanconi features were noted (Easton_2016). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 3/60466 cases, but was also found in 3/53461 controls (Dorling_2021 through LOVD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 26921362, 29368341). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 17, 2023	The p.S197F variant (also known as c.590C>T), located in coding exon 5 of the BRIP1 gene, results from a C to T substitution at nucleotide position 590. The serine at codon 197 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was observed within individuals with a personal history of breast cancer (Easton DF et al. J Med Genet, 2016 May;53:298-309). This variant was also identified in multiple cohorts of males diagnosed with prostate cancer (Isaacsson Velho P et al. Prostate, 2018 04;78:401-40; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43).This amino acid position is well 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 26, 2022	This missense variant replaces serine with phenylalanine at codon 197 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26921362) and prostate cancer (PMID: 29368341). In a large breast cancer case-control study, this variant has been observed in 3/60463 cases and 3/53458 controls; OR=0.884 (95%CI 0.178 to 4.381); p-value=1 (PMID: 33471991 - Leiden Open Variation Database DB-ID BRIP1_000673). This variant has also been identified in 9/282754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 05, 2023

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 197 of the BRIP1 protein (p.Ser197Phe). This variant is present in population databases (rs533184563, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 26921362, 29368341). ClinVar contains an entry for this variant (Variation ID: 142178). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative 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. -

BRIP1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 10, 2024

The BRIP1 c.590C>T variant is predicted to result in the amino acid substitution p.Ser197Phe. This variant has been reported as having uncertain significance in a patient with recurrent or metastatic adenocarcinoma of the prostate (Table S1, Isaacsson Velho et al. 2018. PubMed ID: 29368341) and has also been reported in a study of breast cancer patients (Tables S1 and S2, Easton et al. 2016. PubMed ID: 26921362); however, the variant has also been described in unaffected controls (Dorling et al. 2021. PubMed ID: 33471991, supplementary data, reported as 59924499_G_A). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142178/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.088

T

BayesDel_noAF

Benign

-0.18

CADD

Benign

19

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.84

D

LIST_S2

Benign

0.65

T;T

M_CAP

Uncertain

0.19

D

MetaRNN

Uncertain

0.59

D;D

MetaSVM

Uncertain

0.055

D

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Benign

0.32

T

PROVEAN

Benign

-2.1

N;.

REVEL

Uncertain

0.40

Sift

Uncertain

0.018

D;.

Sift4G

Uncertain

0.059

T;T

Polyphen

1.0

D;.

Vest4

0.39

MVP

0.92

MPC

0.21

ClinPred

0.36

T

GERP RS

4.3

Varity_R

0.089

gMVP

0.47

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.

rs533184563

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