chr17-61716002-C-T

Variant names:

• chr17-61716002-C-T
• rs45468199
• NM_032043.3:c.2441G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 BP4

The NM_032043.3(BRIP1):​c.2441G>A​(p.Arg814His) variant causes a missense change. The variant allele was found at a frequency of 0.0000371 in 1,456,798 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R814C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:1
• Conservation: PhyloP100: 3.62
• Publications: 8 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 1 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.34205124).

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.2441G>A	p.Arg814His	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.2441G>A	p.Arg814His	missense	Exon 17 of 20	ENSP00000259008.2	Q9BX63-1
	BRIP1	ENST00000682453.1		c.2441G>A	p.Arg814His	missense	Exon 18 of 21	ENSP00000506943.1	Q9BX63-1
	BRIP1	ENST00000683039.1		c.2441G>A	p.Arg814His	missense	Exon 18 of 21	ENSP00000508303.1	Q9BX63-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000320 AC: 8 AN: 250268 AF XY: 0.0000369

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000371 AC: 54 AN: 1456798 Hom.: 0 Cov.: 30 AF XY: 0.0000442 AC XY: 32 AN XY: 724460

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39408

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.0000478 AC: 53 AN: 1109252

Other (OTH) AF: 0.00 AC: 0 AN: 60132

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Hereditary cancer-predisposing syndrome (3)
-	2	-	Familial cancer of breast (2)
-	2	-	not provided (2)
-	1	-	Familial cancer of breast;C1836860:Fanconi anemia complementation group J (1)
-	1	-	Familial ovarian cancer (1)
-	1	-	Fanconi anemia complementation group J (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	1	-	Malignant tumor of breast (1)
-	1	-	not specified (1)
-	1	-	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.1	L
PhyloP100		3.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.31
Sift	Benign	0.22	T
Sift4G	Benign	0.26	T
Polyphen		0.92	P
Vest4		0.36
MutPred		0.55		Loss of MoRF binding (P = 0.0446)
MVP		0.97
MPC		0.24
ClinPred		0.14	T
GERP RS		5.6
Varity_R		0.14
gMVP		0.29
Mutation Taster		=89/11	polymorphism

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: rs45468199; hg19: chr17-59793363; COSMIC: COSV51995826;