17-61793628-C-T

Variant names:

• chr17-61793628-C-T
• rs200062099
• NM_032043.3:c.1442G>A

Variant summary

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

The NM_032043.3(BRIP1):​c.1442G>A​(p.Gly481Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000079 in 1,607,944 control chromosomes in the GnomAD database, including 1 homozygotes. 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. G481S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (1 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:5
• Conservation: PhyloP100: 6.97
• Publications: 22 publications found

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

ACMG classification

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

• BP6: Variant 17-61793628-C-T is Benign according to our data. Variant chr17-61793628-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141975.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.1442G>A	p.Gly481Asp	missense_variant	Exon 10 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.1442G>A	p.Gly481Asp	missense_variant	Exon 10 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

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: 0.000119 AC: 29 AN: 243572 AF XY: 0.000107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00155

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000915

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000852 AC: 124 AN: 1455900 Hom.: 1 Cov.: 30 AF XY: 0.0000829 AC XY: 60 AN XY: 723844

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00309 AC: 122 AN: 39484

South Asian (SAS) AF: 0.00 AC: 0 AN: 85460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5520

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108818

Other (OTH) AF: 0.00 AC: 0 AN: 60112

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152044 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74252

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:3

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 481 of the BRIP1 protein (p.Gly481Asp). This variant is present in population databases (rs200062099, gnomAD 0.1%). This missense change has been observed in individual(s) with breast cancer (PMID: 26689913, 26790966, 27701467, 29263802, 29667044). ClinVar contains an entry for this variant (Variation ID: 141975). 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.

May 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 28, 2025

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1 Benign:2

Aug 13, 2019

Leiden Open Variation Database

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.

Mar 19, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRIP1 c.1442G>A (p.Gly481Asp) results in a non-conservative amino acid change in 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 0.00012 in 243572 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 24 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1442G>A has been reported in the literature in the TGCA cohort (Lu_2015), in studies reporting cohorts of individuals of east asian ancestry undergoing multigene panel testing and in unaffected control cohorts (example, Wong_2016, Kim_2016, Hayano_2016, Ohmoto_2018, Fujita_2020). One of these studies has recently rendered a final classification for this variant a benign among individuals undergoing population-based screening for hereditary colorectal cancer variants in Japan (Fujita_2020). Therefore, none of the ascertained reports provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and the LOVD have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (LOVD database-benign, n=1; likely benign, n=1, VUS, n=6). Most submitters reporting a VUS classification cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Dec 29, 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.

May 11, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 09, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Familial cancer of breast Uncertain:1 Benign:1

Mar 01, 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.

Jan 23, 2024

Baylor Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ovarian cancer;C1836860:Fanconi anemia complementation group J Uncertain:1

Apr 02, 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.

BRIP1-related disorder Uncertain:1

Apr 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRIP1 c.1442G>A variant is predicted to result in the amino acid substitution p.Gly481Asp. This variant has been identified in individuals with prostate and breast cancer (Lu et al. 2015. PubMed ID: 26689913; Hayano et al. 2016. PubMed ID: 27701467; Kim et al. 2016. PubMed ID: 26790966). This variant is reported in 0.15% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/141975/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Fanconi anemia complementation group J Uncertain:1

Jun 12, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

not provided Uncertain:1

Aug 24, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with breast cancer, prostate cancer, or other cancers, as well as in unaffected controls (PMID: 26689913, 27498913, 27701467, 26790966, 29263802, 29667044, 30723762, 33309985, 32068069, 33471991, 36243179); 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: 22578220, 33309985, 31214711, 32566746, 32068069, 24686850, 26790966, 24163242, 25256751, 26689913, 26709662, 27498913, 27701467, 30055942, 29263802, 30723762, 33471991, 29667044, 35534218, 36243179)

Hereditary breast ovarian cancer syndrome Uncertain:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.8	M;M
PhyloP100		7.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.6	D;.
REVEL	Pathogenic	0.76
Sift	Benign	0.059	T;.
Sift4G	Benign	0.085	T;T
Vest4		0.87
ClinPred		0.44	T
GERP RS		5.2
Varity_R		0.58
gMVP		0.77
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs200062099; hg19: chr17-59870989; COSMIC: COSV51994226;