rs201869624

chr17-61716003-G-Achr17-61716003-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

The NM_032043.3(BRIP1):c.2440C>T(p.Arg814Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,608,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R814H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:10 O:1
• Conservation: PhyloP100: 3.58

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_032043.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.020456642).
• BP6: Variant 17-61716003-G-A is Benign according to our data. Variant chr17-61716003-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133755.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Uncertain_significance=5, Benign=4, Likely_benign=6}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000256 (39/152120) while in subpopulation EAS AF= 0.00578 (30/5186). AF 95% confidence interval is 0.00416. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.2440C>T	p.Arg814Cys	missense_variant	17/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.2440C>T	p.Arg814Cys	missense_variant	17/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 39 AN: 152006 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00577

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000472 AC: 118 AN: 250258 Hom.: 0 AF XY: 0.000443 AC XY: 60 AN XY: 135316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00529

Gnomad SAS exome AF: 0.000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000157 AC: 228 AN: 1456774 Hom.: 0 Cov.: 30 AF XY: 0.000179 AC XY: 130 AN XY: 724466

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00340

Gnomad4 SAS exome AF: 0.000811

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000901

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152120 Hom.: 0 Cov.: 31 AF XY: 0.000363 AC XY: 27 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00578

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000379 Hom.: 1

Bravo AF: 0.000238

ExAC AF: 0.000478 AC: 58

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 08, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 26, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 18, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 27, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 17, 2020	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:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 09, 2016	Variant summary: The BRIP1 c.2440C>T (p.Arg814Cys) variant located in the P-loop containing nucleoside triphosphate hydrolase and ATP-dependent helicase, C-terminal domains (via InterPro) causes a missense change involving a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 58/120652 (1/2080), predominantly in the East Asian cohort, 47/8492 (1/180), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic BRIP1 variant of 1/16000. Therefore, suggesting the variant is a common polymorphism found in population(s) of East Asian origin. The variant of interest has been reported in multiple affected individuals via publications as a germline and somatic mutation. In addition multiple clinical diagnostic laboratories cite the variant with conflicting classifications of "uncertain significance" or "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "Likely Benign." -
Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 13, 2019	Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRIP1 p.Arg814Cys variant was identified in 3 of 1382 proband chromosomes (frequency: 0.002) from individuals or families with breast, colorectal cancer (Lin 2016, Ng 2016, Pearlman 2016). The variant was also identified in dbSNP (ID: rs201869624) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx; classified as likely benign by Invitae), Clinvitae (classified as uncertain significance by ClinVar, Invitae). The variant was not identified in the Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 117 of 276074 chromosomes at a frequency of 0.000424 in east Asian and south Asian populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg814 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Neoplasm of ovary;C1836860:Fanconi anemia complementation group J Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Dec 14, 2016

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 23, 2023

- -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Fanconi anemia complementation group J Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Familial cancer of breast Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Mar 02, 2023

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.020	T;T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.019	D;.
Sift4G	Benign	0.074	T;T
Polyphen		1.0	D;.
Vest4		0.71
MVP		0.99
MPC		0.77
ClinPred		0.17	T
GERP RS		5.6
Varity_R		0.54
gMVP		0.43

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

Other links and lift over

dbSNP: rs201869624; hg19: chr17-59793364;