chr17-61780946-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_032043.3(BRIP1):c.1688A>G(p.Asp563Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D563N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 5.34

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

familial ovarian cancer
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Fanconi anemia
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
Fanconi anemia complementation group J
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary breast carcinoma
Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
colorectal adenoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 17-61780946-T-C is Benign according to our data. Variant chr17-61780946-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 232167. Variant chr17-61780946-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 232167. Variant chr17-61780946-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 232167. Variant chr17-61780946-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 232167. Variant chr17-61780946-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 232167. Variant chr17-61780946-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 232167. Variant chr17-61780946-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 232167. Variant chr17-61780946-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 232167. Variant chr17-61780946-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 232167. Variant chr17-61780946-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 232167. Variant chr17-61780946-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 232167. Variant chr17-61780946-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 232167. Variant chr17-61780946-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 232167. Variant chr17-61780946-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 232167.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3 link	c.1688A>G	p.Asp563Gly	missense_variant	Exon 12 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.1688A>G	p.Asp563Gly	missense_variant	Exon 12 of 20	1	NM_032043.3	ENSP00000259008.2		Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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:

0.0000517

AC:

AN:

251378

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000707

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000378

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111968

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00000657

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:2

Aug 02, 2022

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRIP1 c.1688A>G (p.Asp563Gly) missense change has a maximum subpopulation frequency of 0.071% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with hereditary breast and ovarian cancer or Fanconi anemia. In summary, the evidence currently available is insufficient to determine the role of this variant in disease. It has therefore been classified as of uncertain significance. -

Oct 10, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Mar 18, 2021

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 10, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 specified

Uncertain:1

Mar 14, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRIP1 c.1688A>G (p.Asp563Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251378 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRIP1 causing Hereditary Breast And Ovarian Cancer Syndrome (5.2e-05 vs 6.3e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1688A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=2; Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Jun 29, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in cases and controls in a colorectal cancer study, as well as an individual with esophageal cancer in published literature (Deng et al., 2019; Fujita et al., 2020); This variant is associated with the following publications: (PMID: 25401301, 30833958, 32091409, 33309985) -

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

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.

Eigen

Benign

0.092

Eigen_PC

Benign

0.064

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

T;T

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.7

M;M

PhyloP100

5.3

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.8

D;.

REVEL

Uncertain

0.35

Sift

Benign

0.087

T;.

Sift4G

Benign

0.099

T;T

Polyphen

0.91

P;.

Vest4

0.79

MutPred

0.40

Loss of stability (P = 0.0376);Loss of stability (P = 0.0376);

MVP

0.88

MPC

0.71

ClinPred

0.34

GERP RS

4.1

Varity_R

0.14

gMVP

0.69

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over