rs1799949

Variant names:

• chr17-43093449-G-A
• rs1799949
• NM_007294.4:c.2082C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43093449-G-A
• chr17-43093449-G-C
• chr17-43093449-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_007294.4(BRCA1):​c.2082C>T​(p.Ser694Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 1,613,688 control chromosomes in the GnomAD database, including 93,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.32 (7899 hom., cov: 32)
  • Exomes 𝑓: 0.34 (85510 hom.)
• Consequence: BRCA1 NM_007294.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:32 O:1
• Conservation: PhyloP100: -0.00100
• Publications: 149 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-43093449-G-A is Benign according to our data. Variant chr17-43093449-G-A is described in ClinVar as Benign. ClinVar VariationId is 125536.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-0.001 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.477 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.2082C>T	p.Ser694Ser	synonymous	Exon 10 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.2082C>T	p.Ser694Ser	synonymous	Exon 10 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.2082C>T	p.Ser694Ser	synonymous	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.2082C>T	p.Ser694Ser	synonymous	Exon 10 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.2082C>T	p.Ser694Ser	synonymous	Exon 10 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.2082C>T	p.Ser694Ser	synonymous	Exon 10 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47951 AN: 151894 Hom.: 7893 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.353 AC: 88547 AN: 251110 AF XY: 0.361

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.317

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.379

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.324

Gnomad OTH exome AF: 0.346

GnomAD4 exome AF: 0.338 AC: 494427 AN: 1461676 Hom.: 85510 Cov.: 48 AF XY: 0.343 AC XY: 249675 AN XY: 727134

African (AFR) AF: 0.230 AC: 7712 AN: 33478

American (AMR) AF: 0.320 AC: 14309 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 9573 AN: 26132

East Asian (EAS) AF: 0.353 AC: 13997 AN: 39688

South Asian (SAS) AF: 0.499 AC: 43063 AN: 86242

European-Finnish (FIN) AF: 0.396 AC: 21126 AN: 53346

Middle Eastern (MID) AF: 0.371 AC: 2138 AN: 5766

European-Non Finnish (NFE) AF: 0.326 AC: 362081 AN: 1111930

Other (OTH) AF: 0.338 AC: 20428 AN: 60390

GnomAD4 genome AF: 0.316 AC: 47985 AN: 152012 Hom.: 7899 Cov.: 32 AF XY: 0.322 AC XY: 23939 AN XY: 74294

African (AFR) AF: 0.233 AC: 9664 AN: 41454

American (AMR) AF: 0.328 AC: 5016 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1243 AN: 3470

East Asian (EAS) AF: 0.369 AC: 1913 AN: 5178

South Asian (SAS) AF: 0.493 AC: 2376 AN: 4818

European-Finnish (FIN) AF: 0.404 AC: 4264 AN: 10550

Middle Eastern (MID) AF: 0.346 AC: 101 AN: 292

European-Non Finnish (NFE) AF: 0.330 AC: 22441 AN: 67960

Other (OTH) AF: 0.336 AC: 709 AN: 2112

Alfa AF: 0.294 Hom.: 13436

Bravo AF: 0.301

Asia WGS AF: 0.411 AC: 1427 AN: 3478

EpiCase AF: 0.322

EpiControl AF: 0.331

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	11	Breast-ovarian cancer, familial, susceptibility to, 1 (12)
-	-	8	not specified (8)
-	-	4	Hereditary breast ovarian cancer syndrome (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	2	Familial cancer of breast (2)
-	-	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
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.47
PhyloP100		-0.0010
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs1799949; hg19: chr17-41245466; COSMIC: COSV58784419; COSMIC: COSV58784419;