NM_007294.4:c.4992C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_007294.4(BRCA1):c.4992C>T(p.Leu1664Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,610,376 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L1664L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:1B:17

Conservation

PhyloP100: -0.281

Publications

7 publications found

Variant links:

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

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 17-43067690-G-A is Benign according to our data. Variant chr17-43067690-G-A is described in ClinVar as Benign. ClinVar VariationId is 136551.Status of the report is reviewed_by_expert_panel, 3 stars.

BP7

Synonymous conserved (PhyloP=-0.281 with no splicing effect.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCA1	NM_007294.4	MANE Select	c.4992C>T	p.Leu1664Leu	synonymous	Exon 16 of 23	NP_009225.1	P38398-1
BRCA1	NM_001407581.1		c.5058C>T	p.Leu1686Leu	synonymous	Exon 17 of 24	NP_001394510.1	A0A2R8Y7V5
BRCA1	NM_001407582.1		c.5058C>T	p.Leu1686Leu	synonymous	Exon 17 of 24	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.4992C>T	p.Leu1664Leu	synonymous	Exon 16 of 23	ENSP00000350283.3	P38398-1
BRCA1	ENST00000471181.7	TSL:1	c.5055C>T	p.Leu1685Leu	synonymous	Exon 17 of 24	ENSP00000418960.2	P38398-7
BRCA1	ENST00000470026.6	TSL:1	c.4992C>T	p.Leu1664Leu	synonymous	Exon 16 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.000507

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000111

AC:

AN:

251306

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000590

AC:

AN:

1458354

Hom.:

Cov.:

AF XY:

0.0000496

AC XY:

AN XY:

725750

show subpopulations

African (AFR)

AF:

0.00198

AC:

AN:

33392

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000721

AC:

AN:

1108868

Other (OTH)

AF:

0.0000829

AC:

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000507

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.00181

AC:

AN:

41390

American (AMR)

AF:

0.00

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000724

Hom.:

Bravo

AF:

0.000642

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Hereditary cancer-predisposing syndrome (3)

Breast-ovarian cancer, familial, susceptibility to, 1 (2)

Hereditary breast ovarian cancer syndrome (2)

BRCA1-related disorder (1)

Familial cancer of breast (1)

Hereditary breast ovarian cancer syndrome;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1 (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.63

(source)

DANN

Benign

0.45

PhyloP100

-0.28

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

3.0

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over