rs45589637

chr17-61744469-C-Achr17-61744469-C-Gchr17-61744469-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_032043.3(BRIP1):c.2220G>T(p.Gln740His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000575 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. Q740E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:12 O:2
• Conservation: PhyloP100: 0.274

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07559261).
• BP6: Variant 17-61744469-C-A is Benign according to our data. Variant chr17-61744469-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133752.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=12, Likely_benign=12, not_provided=2}. Variant chr17-61744469-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.2220G>T	p.Gln740His	missense_variant	15/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.2220G>T	p.Gln740His	missense_variant	15/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000537 AC: 135 AN: 251286 Hom.: 0 AF XY: 0.000434 AC XY: 59 AN XY: 135822

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000643

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000582 AC: 851 AN: 1461672 Hom.: 0 Cov.: 31 AF XY: 0.000556 AC XY: 404 AN XY: 727138

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.000674

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74434

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000669 Hom.: 1

Bravo AF: 0.000676

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000818

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14 Benign:12 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	This variant is associated with the following publications: (PMID: 28202063, 31159747, 25980754, 24728327, 26534844, 27547810, 26315354, 28528518, 26921362, 27978560, 28678401, 28767289, 31822495, 32039725, 31658756, 33115781) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	BRIP1: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 20, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 02, 2016	Variant summary: The BRIP1 c.2220G>T (p.Gln740His) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 58/133810 control chromosomes at a frequency of 0.0004335, which is approximately 7 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this variant is likely a benign polymorphism. This variant has been reported in multiple cancer patients, however, a case-control study showed that this variant was not associated with breast cancer (OR=0.638, P=0.49, Haiman_2013). In addition, two patients carry the variant of interest and a pathogenic variant, homozygous MUTYH c.1187G>A/p.Gly396Asp and PALB2 c.3113G>A/W1038X, respectively (Yurgelun_2015, Kahn_2016), suggesting the variant of interest may be benign. On the other hand, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 11, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 09, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 15, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 20, 2020	- -

Fanconi anemia complementation group J Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 18, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP1. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 23, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 09, 2021	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Familial cancer of breast Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 02, 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	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jun 15, 2021	ACMG classification criteria: BS1 strong -

not specified Uncertain:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 20, 2016	- -

BRIP1-related disorder Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 17, 2023	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 05, 2019	The BRIP1 c.2220G>T (p.Gln740His) missense variant has been reported in at least four studies in which it is found in a heterozygous state in total of three individuals with Lynch syndrome, one of whom also carried a homozygous variant in the MUTYH gene (Bodian et al. 2014; Ramus et al. 2015; Yurgelun et al. 2015; Easton et al. 2016). The p.Gln740His variant was identified in a heterozygous state in six of 3431 controls and is reported at a frequency of 0.00140 in the Latino population of the Genome Aggregation Database. Based on the limited evidence, the p.Gln740His variant is classified as a variant of unknown significance but suspicious for pathogenicity for BRIP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Likely benign and reported on 10-31-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Neoplasm of ovary Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Aug 23, 2016

- -

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.Gln740His variant was identified in 32 of 48608 proband chromosomes (frequency: 0.0007) from individuals or families with breast, ovarian cancer or Lynch syndrome and was present in 7 of 14818 control chromosomes (frequency: 0.0006) from healthy individuals (Easton 2016, Jalkh 2017, Li 2015, Penkert 2018, Ramus 2015, Tung 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs45589637) as "With other allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and nine other submitters; as likely benign by Integrated Genetics/Laboratory Corporation of America and GeneDx). The variant was identified in control databases in 144 of 277004 chromosomes at a frequency of 0.0005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24024 chromosomes (freq: 0.00008), Other in 4 of 6460 chromosomes (freq: 0.0006), Latino in 48 of 34414 chromosomes (freq: 0.001), European in 82 of 126532 chromosomes (freq: 0.0007), Ashkenazi Jewish in 2 of 10148 chromosomes (freq: 0.0002), Finnish in 6 of 25780 chromosomes (freq: 0.0002); it was not observed in the East Asian, and South Asian populations. The p.Gln740 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 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -

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

Nov 02, 2022

- -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	19
Dann	Benign	0.94
DEOGEN2	Uncertain	0.65	D;.
Eigen	Benign	-0.037
Eigen_PC	Benign	-0.081
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.076	T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.2	N;.
REVEL	Uncertain	0.43
Sift	Benign	0.045	D;.
Sift4G	Uncertain	0.035	D;D
Polyphen		0.97	D;.
Vest4		0.41
MutPred		0.38		Gain of catalytic residue at D744 (P = 0.0907);Gain of catalytic residue at D744 (P = 0.0907);
MVP		0.89
MPC		0.42
ClinPred		0.041	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.58

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: rs45589637; hg19: chr17-59821830;