17-61685986-A-G

Variant names:

• chr17-61685986-A-G
• rs4986764
• NM_032043.3:c.2755T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032043.3(BRIP1):​c.2755T>C​(p.Ser919Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 1,613,258 control chromosomes in the GnomAD database, including 289,538 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S919A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.61 (29085 hom., cov: 31)
  • Exomes 𝑓: 0.59 (260453 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21 O:1
• Conservation: PhyloP100: 0.201
• Publications: 110 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3598933E-6).
• BP6: Variant 17-61685986-A-G is Benign according to our data. Variant chr17-61685986-A-G is described in ClinVar as Benign. ClinVar VariationId is 133756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

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.2755T>C	p.Ser919Pro	missense	Exon 19 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.2755T>C	p.Ser919Pro	missense	Exon 19 of 20	ENSP00000259008.2	Q9BX63-1
	BRIP1	ENST00000682453.1		c.2755T>C	p.Ser919Pro	missense	Exon 20 of 21	ENSP00000506943.1	Q9BX63-1
	BRIP1	ENST00000683039.1		c.2755T>C	p.Ser919Pro	missense	Exon 20 of 21	ENSP00000508303.1	Q9BX63-1

Frequencies

GnomAD3 genomes AF: 0.612 AC: 92858 AN: 151790 Hom.: 29042 Cov.: 31

Gnomad AFR AF: 0.672

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.739

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.633

GnomAD2 exomes AF: 0.602 AC: 151298 AN: 251386 AF XY: 0.588

Gnomad AFR exome AF: 0.674

Gnomad AMR exome AF: 0.799

Gnomad ASJ exome AF: 0.590

Gnomad EAS exome AF: 0.715

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.588

Gnomad OTH exome AF: 0.622

GnomAD4 exome AF: 0.593 AC: 866589 AN: 1461350 Hom.: 260453 Cov.: 57 AF XY: 0.588 AC XY: 427396 AN XY: 727012

African (AFR) AF: 0.673 AC: 22521 AN: 33472

American (AMR) AF: 0.790 AC: 35317 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 15427 AN: 26132

East Asian (EAS) AF: 0.741 AC: 29418 AN: 39682

South Asian (SAS) AF: 0.460 AC: 39632 AN: 86238

European-Finnish (FIN) AF: 0.430 AC: 22990 AN: 53418

Middle Eastern (MID) AF: 0.657 AC: 3790 AN: 5766

European-Non Finnish (NFE) AF: 0.595 AC: 661511 AN: 1111540

Other (OTH) AF: 0.596 AC: 35983 AN: 60378

GnomAD4 genome AF: 0.612 AC: 92966 AN: 151908 Hom.: 29085 Cov.: 31 AF XY: 0.606 AC XY: 45004 AN XY: 74216

African (AFR) AF: 0.672 AC: 27839 AN: 41426

American (AMR) AF: 0.739 AC: 11282 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 2101 AN: 3472

East Asian (EAS) AF: 0.721 AC: 3722 AN: 5162

South Asian (SAS) AF: 0.459 AC: 2216 AN: 4824

European-Finnish (FIN) AF: 0.408 AC: 4295 AN: 10528

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.584 AC: 39645 AN: 67918

Other (OTH) AF: 0.633 AC: 1333 AN: 2106

Alfa AF: 0.600 Hom.: 81243

Bravo AF: 0.643

TwinsUK AF: 0.588 AC: 2182

ALSPAC AF: 0.601 AC: 2316

ESP6500AA AF: 0.661 AC: 2913

ESP6500EA AF: 0.589 AC: 5065

ExAC AF: 0.597 AC: 72503

Asia WGS AF: 0.540 AC: 1879 AN: 3476

EpiCase AF: 0.597

EpiControl AF: 0.610

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (7)
-	-	3	Familial cancer of breast (3)
-	-	3	Fanconi anemia complementation group J (3)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	1	Familial cancer of breast;C1836860:Fanconi anemia complementation group J (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.9
DANN	Benign	0.90
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0000014	T
MetaSVM	Benign	-0.94	T
PhyloP100		0.20
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.088
Sift	Benign	0.15	T
Sift4G	Benign	0.37	T
Vest4		0.061
MPC		0.20
ClinPred		0.0039	T
GERP RS		0.71
Varity_R		0.056
gMVP		0.20
Mutation Taster		=100/0	polymorphism (auto)

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: rs4986764; hg19: chr17-59763347; COSMIC: COSV51995396;