rs799917

Variant names:

• chr17-43092919-G-A
• rs799917
• NM_007294.4:c.2612C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43092919-G-A
• chr17-43092919-G-C
• chr17-43092919-G-T

Variant summary

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

The NM_007294.4(BRCA1):​c.2612C>T​(p.Pro871Leu) variant causes a missense change. The variant allele was found at a frequency of 0.376 in 1,613,362 control chromosomes in the GnomAD database, including 124,333 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. P871S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.49 (21276 hom., cov: 32)
  • Exomes 𝑓: 0.36 (103057 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel B:37 O:1
• Conservation: PhyloP100: 4.25
• Publications: 368 publications found

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

BRCA1 Gene-Disease associations (from GenCC):

• BRCA1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.915395E-7).
• BP6: Variant 17-43092919-G-A is Benign according to our data. Variant chr17-43092919-G-A is described in ClinVar as Benign. ClinVar VariationId is 41812.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. 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
	BRCA1	NM_007294.4	MANE Select	c.2612C>T	p.Pro871Leu	missense	Exon 10 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.2612C>T	p.Pro871Leu	missense	Exon 10 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.2612C>T	p.Pro871Leu	missense	Exon 10 of 24	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.2612C>T	p.Pro871Leu	missense	Exon 10 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.2612C>T	p.Pro871Leu	missense	Exon 10 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.2612C>T	p.Pro871Leu	missense	Exon 10 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.487 AC: 74015 AN: 151956 Hom.: 21221 Cov.: 32

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.459

GnomAD2 exomes AF: 0.404 AC: 101374 AN: 251034 AF XY: 0.402

Gnomad AFR exome AF: 0.825

Gnomad AMR exome AF: 0.348

Gnomad ASJ exome AF: 0.377

Gnomad EAS exome AF: 0.379

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.334

Gnomad OTH exome AF: 0.378

GnomAD4 exome AF: 0.364 AC: 532630 AN: 1461288 Hom.: 103057 Cov.: 62 AF XY: 0.368 AC XY: 267321 AN XY: 726932

African (AFR) AF: 0.831 AC: 27827 AN: 33476

American (AMR) AF: 0.356 AC: 15931 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 9690 AN: 26130

East Asian (EAS) AF: 0.353 AC: 14011 AN: 39684

South Asian (SAS) AF: 0.528 AC: 45503 AN: 86250

European-Finnish (FIN) AF: 0.397 AC: 21082 AN: 53062

Middle Eastern (MID) AF: 0.425 AC: 2454 AN: 5768

European-Non Finnish (NFE) AF: 0.335 AC: 372640 AN: 1111814

Other (OTH) AF: 0.389 AC: 23492 AN: 60384

GnomAD4 genome AF: 0.487 AC: 74125 AN: 152074 Hom.: 21276 Cov.: 32 AF XY: 0.488 AC XY: 36241 AN XY: 74336

African (AFR) AF: 0.811 AC: 33664 AN: 41522

American (AMR) AF: 0.390 AC: 5962 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1265 AN: 3472

East Asian (EAS) AF: 0.370 AC: 1913 AN: 5168

South Asian (SAS) AF: 0.522 AC: 2521 AN: 4826

European-Finnish (FIN) AF: 0.407 AC: 4287 AN: 10546

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23151 AN: 67946

Other (OTH) AF: 0.462 AC: 977 AN: 2114

Alfa AF: 0.353 Hom.: 37582

Bravo AF: 0.497

TwinsUK AF: 0.347 AC: 1288

ALSPAC AF: 0.344 AC: 1324

ESP6500AA AF: 0.800 AC: 3525

ESP6500EA AF: 0.336 AC: 2889

ExAC AF: 0.410 AC: 49775

Asia WGS AF: 0.473 AC: 1644 AN: 3478

EpiCase AF: 0.333

EpiControl AF: 0.342

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	13	Breast-ovarian cancer, familial, susceptibility to, 1 (13)
-	-	8	not specified (9)
-	-	4	Hereditary breast ovarian cancer syndrome (4)
-	-	4	not provided (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Familial cancer of breast (2)
-	-	1	BRCA1-related cancer predisposition (1)
-	-	1	Breast carcinoma (1)
-	-	1	Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	9.9e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-3.4	N
PhyloP100		4.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	5.7	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.31
MPC		0.082
ClinPred		0.0025	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.020
gMVP		0.084
Mutation Taster		=85/15	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.010		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: rs799917; hg19: chr17-41244936; COSMIC: COSV58784386; COSMIC: COSV58784386;