dbSNP rs764711572: BRIP1:p.Asp400Tyr (chr17-61799242-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_032043.3(BRIP1):c.1198G>T(p.Asp400Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,376 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 (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.09

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 Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3 link	c.1198G>T	p.Asp400Tyr	missense_variant	Exon 9 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.1198G>T	p.Asp400Tyr	missense_variant	Exon 9 of 20	1	NM_032043.3	ENSP00000259008.2		Q9BX63-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250882

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135572

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461376

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726984

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:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Sep 20, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with tyrosine at codon 400 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754) and in two individuals with melanoma (PMID: 30414346). This variant has been identified in 3/250882 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. -

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D400Y variant (also known as c.1198G>T), located in coding exon 8 of the BRIP1 gene, results from a G to T substitution at nucleotide position 1198. The aspartic acid at codon 400 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been identified in 2/976 alleles from a cohort of Dutch melanomaprone families (Potjer TP et al. Int. J. Cancer, 2019 05;144:2453-2464). This alteration was detected in 3/1197 patients with breast cancer who underwent genetic testing (Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified

Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Uncertain:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 400 of the BRIP1 protein (p.Asp400Tyr). This variant is present in population databases (rs764711572, gnomAD 0.003%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754, 30414346). ClinVar contains an entry for this variant (Variation ID: 216785). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRIP1 protein function. 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

Mar 07, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast cancer, melanoma, and a Lynch syndrome-associated cancer and/or polyps (Yurgelun et al., 2015; Weber-Lassalle et al., 2018; Potjer et al., 2019; Abdel-Razeq et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25980754, 30414346, 29368626, 35402282) -

Familial ovarian cancer

Uncertain:1

Dec 13, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast

Uncertain:1

Sep 06, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

4.1

H;H

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-8.0

D;.

REVEL

Uncertain

0.58

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.77

MutPred

0.56

Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);

MVP

0.97

MPC

0.75

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.98

gMVP

0.78

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