rs1259933364

Positions:

• chr17-61780929-C-A
• chr17-61780929-C-G
• chr17-61780929-C-T

Variant summary

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

The NM_032043.3(BRIP1):​c.1705G>T​(p.Gly569Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G569E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.08

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.1705G>T	p.Gly569Trp	missense_variant	12/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.1705G>T	p.Gly569Trp	missense_variant	12/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461740 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727172

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 14, 2023

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. This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 569 of the BRIP1 protein (p.Gly569Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1345086). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2021

The p.G569W variant (also known as c.1705G>T), located in coding exon 11 of the BRIP1 gene, results from a G to T substitution at nucleotide position 1705. The glycine at codon 569 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is not well 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	0.053
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.57	T;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	0.016	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.96	D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.021	D;D
Polyphen		0.99	D;.
Vest4		0.47
MutPred		0.61		Gain of MoRF binding (P = 0.0287);Gain of MoRF binding (P = 0.0287);
MVP		0.85
MPC		0.73
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.092
gMVP		0.85

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: rs1259933364; hg19: chr17-59858290;