17-61693495-T-C

Position:

• chr17-61693495-T-C

Variant summary

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

The NM_032043.3(BRIP1):​c.2510A>G​(p.Asn837Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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:2
• Conservation: PhyloP100: 2.58

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34034488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.2510A>G	p.Asn837Ser	missense_variant	18/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.2510A>G	p.Asn837Ser	missense_variant	18/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jan 02, 2018

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: "Tolerated"; PolyPhen-2: "Possibly 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 asparagine with serine at codon 837 of the BRIP1 protein (p.Asn837Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2017

The p.N837S variant (also known as c.2510A>G), located in coding exon 17 of the BRIP1 gene, results from an A to G substitution at nucleotide position 2510. The asparagine at codon 837 is replaced by serine, an amino acid with highly similar 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Uncertain	0.34
Sift	Benign	0.32	T;.
Sift4G	Benign	0.55	T;T
Polyphen		0.58	P;.
Vest4		0.44
MutPred		0.45		Gain of phosphorylation at N837 (P = 0.0996);Gain of phosphorylation at N837 (P = 0.0996);
MVP		0.99
MPC		0.37
ClinPred		0.86	D
GERP RS		5.9
Varity_R		0.15
gMVP		0.43

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: rs1555574810; hg19: chr17-59770856;