rs759031349

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_032043.3(BRIP1):c.689C>T(p.Ser230Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,672 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S230P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:7

Conservation

PhyloP100: 1.64

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07737577).

BP6

Variant 17-61808696-G-A is Benign according to our data. Variant chr17-61808696-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186643.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.689C>T	p.Ser230Leu	missense_variant	7/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.689C>T	p.Ser230Leu	missense_variant	7/20	1	NM_032043.3	P2	Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

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:

0.0000956

AC:

AN:

251036

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000665

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461600

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000827

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000524

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

Bravo

AF:

0.0000416

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 20, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 30, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of ovarian, breast, and other cancers (Ramus et al., 2015; Ring et al., 2016; Quezada Urban et al., 2018; Weitzel et al., 2019; Dharwadkar et al., 2020); This variant is associated with the following publications: (PMID: 26315354, 26921362, 27443514, 30262796, 31658756, 30374176, 31206626, 27535533, 33359728) -

Familial cancer of breast

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	Mar 28, 2018	The BRIP1 variant designated as NM_032043.2:c.689C>T (p.Ser230Leu) is classified as likely benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (RaÃ±ola et al, 2018, PMID:28965303) and gives a likelihood ratio of 1.1 to 1 (Thompson et al, 2003, PMID:12900794), which gives very weak support for this allele being associated with cancer risk. The genomic position is not evolutionarily conserved. The variant is reported to be present in approximately 1 in 800 individuals with Latin American ancestry (exac.broadinstitute.org), which is considered too common in the population to cause high cancer risk. This variant has been classified as likely benign by other laboratories (ClinVar Variation ID: 186643). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BRIP1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 28, 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	Jan 07, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Fanconi anemia complementation group J

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 29, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 19, 2016	- -

Ovarian neoplasm

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Sep 19, 2016

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 19, 2024

Variant summary: BRIP1 c.689C>T (p.Ser230Leu) results in a non-conservative amino acid change located in the Helicase-like, DEXD box c2 type domain (IPR006554) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 251036 control chromosomes, predominantly at a frequency of 0.00067 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Breast Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.689C>T has been reported in the literature as a VUS in individuals undergoing multigene cancer panel testing (e.g. Ramus_2015, Ring_2016, Weitzel_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Breast and/or BRIP1-related Cancer. 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, 26315354, 27443514, 30374176, 31206626). ClinVar contains an entry for this variant (Variation ID: 186643). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.077

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.3

N;.

REVEL

Benign

0.086

Sift

Benign

0.38

T;.

Sift4G

Benign

0.36

T;T

Polyphen

0.0

B;.

Vest4

0.14

MutPred

0.20

Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);

MVP

0.85

MPC

0.14

ClinPred

0.027

GERP RS

3.2

Varity_R

0.019

gMVP

0.40

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