17-61744435-T-G

Variant summary

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

The NM_032043.3(BRIP1):c.2254A>C(p.Lys752Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,422 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K752R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.28

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.2254A>C	p.Lys752Gln	missense_variant	15/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.2254A>C	p.Lys752Gln	missense_variant	15/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461422 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727006

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 27, 2023	The p.K752Q variant (also known as c.2254A>C), located in coding exon 14 of the BRIP1 gene, results from an A to C substitution at nucleotide position 2254. The lysine at codon 752 is replaced by glutamine, an amino acid with similar 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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2023

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 752 of the BRIP1 protein (p.Lys752Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 35171259). ClinVar contains an entry for this variant (Variation ID: 232254). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2021

Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533, 11301010) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	25
Dann	Benign	0.93
DEOGEN2	Uncertain	0.54	D;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.83	L;L
MutationTaster	Benign	0.53	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.9	N;.
REVEL	Uncertain	0.29
Sift	Benign	0.053	T;.
Sift4G	Benign	0.11	T;T
Polyphen		0.99	D;.
Vest4		0.50
MutPred		0.38		Loss of helix (P = 0.0123);Loss of helix (P = 0.0123);
MVP		0.91
MPC		0.68
ClinPred		0.92	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876659651; hg19: chr17-59821796;