NM_007294.4:c.2311T>C

Variant names:

• chr17-43093220-A-G
• rs16940
• NM_007294.4:c.2311T>C

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.2311T>C​(p.Leu771Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,613,608 control chromosomes in the GnomAD database, including 91,981 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 (i.e. L771L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.30 (7355 hom., cov: 32)
  • Exomes 𝑓: 0.34 (84626 hom.)
• Consequence: BRCA1 NM_007294.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:30 O:2
• Conservation: PhyloP100: -0.442
• Publications: 158 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=-0.82).
• BP6: Variant 17-43093220-A-G is Benign according to our data. Variant chr17-43093220-A-G is described in ClinVar as Benign. ClinVar VariationId is 125554.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-0.442 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.476 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.2311T>C	p.Leu771Leu	synonymous	Exon 10 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.2311T>C	p.Leu771Leu	synonymous	Exon 10 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.2311T>C	p.Leu771Leu	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.2311T>C	p.Leu771Leu	synonymous	Exon 10 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.2311T>C	p.Leu771Leu	synonymous	Exon 10 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.2311T>C	p.Leu771Leu	synonymous	Exon 10 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45482 AN: 151856 Hom.: 7352 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.319

GnomAD2 exomes AF: 0.347 AC: 87177 AN: 250946 AF XY: 0.357

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.311

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.379

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.324

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.336 AC: 491155 AN: 1461632 Hom.: 84626 Cov.: 45 AF XY: 0.341 AC XY: 248165 AN XY: 727128

African (AFR) AF: 0.174 AC: 5840 AN: 33478

American (AMR) AF: 0.314 AC: 14057 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 9324 AN: 26132

East Asian (EAS) AF: 0.353 AC: 14001 AN: 39690

South Asian (SAS) AF: 0.498 AC: 42990 AN: 86240

European-Finnish (FIN) AF: 0.396 AC: 21107 AN: 53330

Middle Eastern (MID) AF: 0.366 AC: 2111 AN: 5768

European-Non Finnish (NFE) AF: 0.325 AC: 361646 AN: 1111884

Other (OTH) AF: 0.332 AC: 20079 AN: 60392

GnomAD4 genome AF: 0.299 AC: 45490 AN: 151976 Hom.: 7355 Cov.: 32 AF XY: 0.306 AC XY: 22737 AN XY: 74254

African (AFR) AF: 0.180 AC: 7450 AN: 41468

American (AMR) AF: 0.319 AC: 4875 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1207 AN: 3460

East Asian (EAS) AF: 0.368 AC: 1905 AN: 5172

South Asian (SAS) AF: 0.492 AC: 2370 AN: 4814

European-Finnish (FIN) AF: 0.403 AC: 4253 AN: 10548

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22388 AN: 67938

Other (OTH) AF: 0.324 AC: 683 AN: 2110

Alfa AF: 0.318 Hom.: 19482

Bravo AF: 0.282

Asia WGS AF: 0.405 AC: 1408 AN: 3478

EpiCase AF: 0.321

EpiControl AF: 0.331

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	10	Breast-ovarian cancer, familial, susceptibility to, 1 (11)
-	-	8	not specified (8)
-	-	4	Hereditary breast ovarian cancer syndrome (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	1	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	-0.82
CADD	Benign	1.2
DANN	Benign	0.65
PhyloP100		-0.44
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: rs16940; hg19: chr17-41245237; COSMIC: COSV58786443; COSMIC: COSV58786443;