rs786202760

Positions:

• chr17-61776557-C-A
• chr17-61776557-C-G
• chr17-61776557-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1 PM2 PP3_Strong

The NM_032043.3(BRIP1):​c.1941G>T​(p.Trp647Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 7.11

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 Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_032043.3 (BRIP1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.1941G>T	p.Trp647Cys	missense_variant	14/20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.1941G>T	p.Trp647Cys	missense_variant	14/20	1	NM_032043.3	ENSP00000259008	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461642 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2023	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 647 of the BRIP1 protein (p.Trp647Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25981591). ClinVar contains an entry for this variant (Variation ID: 186189). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRIP1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 29788478). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 05, 2022	- -

Familial cancer of breast Uncertain:2

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	Sep 02, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 11, 2023	This missense variant replaces tryptophan with cysteine at codon 647 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant protein displays reduced helicase activity in an in vitro assay (PMID: 29788478). While this variant has not been reported in individuals affected with BRIP1-associated diseases in the literature, a different variant (c.1941G>C) resulting in the same amino acid change has been reported in individuals affected with Fanconi anemia and breast cancer (PMID: 16116423, 25981591). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 06, 2023	The p.W647C variant (also known as c.1941G>T), located in coding exon 13 of the BRIP1 gene, results from a G to T substitution at nucleotide position 1941. The tryptophan at codon 647 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this alteration was not observed in 706 cases with ovarian cancer or 6341 cases with breast cancer and was observed in 1/36687 healthy controls (Weber-Lassalle N et al. Breast Cancer Res., 2018 01;20:7). Another alteration that results in the same amino acid change (c.1941G>C) has been identified in conjunction with a BRIP1 mutation in an individual diagnosed with Fanconi Anemia complementation group J (FA-J); Western blot demonstrated attenuated protein expression in this individual (Levitus M, Nat. Genet. 2005 Sep; 37(9):934-5). Functional assays indicate this alteration inactivates the helicase activity of the protein, and severely compromises its ability to hydrolyze ATP (Bharti SK et al. Nucleic Acids Res., 2018 Jul;46:6238-6256). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 18, 2021

Variant summary: BRIP1 c.1941G>T (p.Trp647Cys) 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 was absent in 251268 control chromosomes. c.1941G>T has been reported in the literature as a VUS in settings of multigene panel testing in at-least two individuals affected with high-risk features for hereditary breast and ovarian cancer (HBOC) and with a previous uninformative result for BRCA1/2 (Fonfria_2021). One of these individuals reported a triple negative subtype (ER/PR/HER2), while the other reported a triple positive subtype of breast cancer. Furthermore, a different nucleotide substitution, c.1941G>C, that results in an identical amino acid substitution, namely p.Trp647Cys, has been identified along with another FANCJ (BRIP1) allele in an individual affected with Fanconi Anemia (Levitus_2005). Another study reported this specific nucleotide variant in controls but not in breast cancer cases (Weber-Lassalle_2018). Some reports do not specify the exact nucleotide alteration and limit reporting to the affected protein (example, Guo_2016, Bharti_2018 described below). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bharti_2018). The most pronounced variant effect results in <10% of normal helicase activity as evidenced by a decrease in Kcat for ATP hydrolysis in a recombinant FANCJ protein expressing baculovirus system. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Fanconi anemia complementation group J Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Sep 07, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2022

Observed in individuals with breast cancer (Fonfria 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Another substitution, BRIP1 1941G>C, resulting in the same Trp647Cys missense variant has been observed in at least one individual with breast cancer and has been co-observed with a second BRIP1 variant, phase unknown, in an individual with Fanconi anemia (Levitus 2005, Lajus 2015). Furthermore BRIP1 1941G>C (Trp647Cys) has been associated with absent helicase activity and reduced ATP hydrolysis (Bharti 2018).; This variant is associated with the following publications: (PMID: 16116423, 29368626, 23276657, 17145708, 29788478, 25981591, 34204722) -

Ovarian neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Sep 07, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	-0.064	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-10	D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.019	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.81		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.98
MPC		0.87
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.91

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: rs786202760; hg19: chr17-59853918; COSMIC: COSV99370727; COSMIC: COSV99370727;