17-61683702-G-C

Position:

• chr17-61683702-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032043.3(BRIP1):​c.3344C>G​(p.Ser1115Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.25

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]

BRIP1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37074655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.3344C>G	p.Ser1115Cys	missense_variant	20/20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.3344C>G	p.Ser1115Cys	missense_variant	20/20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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	Ambry Genetics	Aug 14, 2017	The p.S1115C variant (also known as c.3344C>G), located in coding exon 19 of the BRIP1 gene, results from a C to G substitution at nucleotide position 3344. The serine at codon 1115 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 06, 2022	This missense variant replaces serine with cysteine at codon 1115 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 reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BRIP1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with cysteine at codon 1115 of the BRIP1 protein (p.Ser1115Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

curation

Leiden Open Variation Database

Aug 13, 2019

Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.47	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.22
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.24
MutPred		0.17		Loss of phosphorylation at S1115 (P = 0.017);
MVP		0.92
MPC		0.63
ClinPred		0.74	D
GERP RS		5.6
Varity_R		0.13
gMVP		0.31

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: rs1419933310; hg19: chr17-59761063;