17-61716003-G-T

Variant names:

• chr17-61716003-G-T
• rs201869624
• NM_032043.3:c.2440C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_032043.3(BRIP1):​c.2440C>A​(p.Arg814Ser) 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. 13/22 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. R814H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• familial ovarian cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• Fanconi anemia complementation group J

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, ClinGen
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 37 uncertain in NM_032043.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29537082).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032043.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	NM_032043.3	MANE Select	c.2440C>A	p.Arg814Ser	missense	Exon 17 of 20	NP_114432.2	Q9BX63-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	ENST00000259008.7	TSL:1 MANE Select	c.2440C>A	p.Arg814Ser	missense	Exon 17 of 20	ENSP00000259008.2	Q9BX63-1
	BRIP1	ENST00000682453.1		c.2440C>A	p.Arg814Ser	missense	Exon 18 of 21	ENSP00000506943.1	Q9BX63-1
	BRIP1	ENST00000683039.1		c.2440C>A	p.Arg814Ser	missense	Exon 18 of 21	ENSP00000508303.1	Q9BX63-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial cancer of breast;C1836860:Fanconi anemia complementation group J (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.071
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	-0.22	N
PhyloP100		3.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.20	N
REVEL	Uncertain	0.33
Sift	Benign	0.54	T
Sift4G	Benign	1.0	T
Polyphen		0.92	P
Vest4		0.41
MutPred		0.52		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.97
MPC		0.21
ClinPred		0.72	D
GERP RS		5.6
Varity_R		0.18
gMVP		0.35

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

Other links and lift over

dbSNP: rs201869624; hg19: chr17-59793364;