rs876658780

Positions:

• chr17-61847195-G-A
• chr17-61847195-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032043.3(BRIP1):​c.533C>T​(p.Thr178Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T178R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 2.18

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13170213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.533C>T	p.Thr178Ile	missense_variant	6/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.533C>T	p.Thr178Ile	missense_variant	6/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251336 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461368 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727008

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 20, 2023	This missense variant replaces threonine with isoleucine at codon 178 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 26315354). This variant has also been identified in 1/251336 chromosomes 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	Sep 14, 2022	The p.T178I variant (also known as c.533C>T), located in coding exon 5 of the BRIP1 gene, results from a C to T substitution at nucleotide position 533. The threonine at codon 178 is replaced by isoleucine, an amino acid with similar properties. In one study, this alteration was observed in 1/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107:). This alteration has been detected in a cohort of 122 patients who underwent multi-gene panel testing for hereditary cancer after having previously tested negative for mutations in BRCA1 and BRCA2 (Yadav S et al. Fam. Cancer, 2017 07;16:319-328). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 04, 2024	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 30, 2021	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2018	This variant is denoted BRIP1 c.533C>T at the cDNA level, p.Thr178Ile (T178I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant was observed in 1/3236 serous ovarian cancer cases and 0/3431 controls (Ramus 2015), and in at least one individual meeting NCCN guidelines for BRCA testing based on their personal and/or family history of cancer (Yadav 2017). BRIP1 Thr178Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRIP1 Thr178Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 09, 2020	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 178 of the BRIP1 protein (p.Thr178Ile). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 26315354, 27878467). ClinVar contains an entry for this variant (Variation ID: 230797). 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 not expected to disrupt BRIP1 protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.52	N;.
REVEL	Benign	0.095
Sift	Benign	0.086	T;.
Sift4G	Benign	0.078	T;T
Polyphen		0.34	B;.
Vest4		0.17
MutPred		0.44		Loss of disorder (P = 0.0568);Loss of disorder (P = 0.0568);
MVP		0.48
MPC		0.24
ClinPred		0.10	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.27

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: rs876658780; hg19: chr17-59924556;