Genetic Variant NM_007294.4:c.*781C>T (chr17-43044897-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007294.4(BRCA1):c.*781C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 471,486 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.0067 ( 17 hom., cov: 30)

Exomes 𝑓: 0.00077 ( 3 hom. )

Consequence

BRCA1
NM_007294.4 3_prime_UTR

Scores

Clinical Significance

Benign reviewed by expert panel B:5

Conservation

PhyloP100: -0.0730

Publications

3 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):

breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Fanconi anemia, complementation group S
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 17-43044897-G-A is Benign according to our data. Variant chr17-43044897-G-A is described in ClinVar as Benign. ClinVar VariationId is 132778.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00667 (988/148092) while in subpopulation AFR AF = 0.0239 (945/39572). AF 95% confidence interval is 0.0226. There are 17 homozygotes in GnomAd4. There are 450 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR,AD gene

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	Effect	Exon Rank	Protein
BRCA1	NM_007294.4	MANE Select	c.*781C>T	3_prime_UTR	Exon 23 of 23	NP_009225.1
BRCA1	NM_001407581.1		c.*781C>T	3_prime_UTR	Exon 24 of 24	NP_001394510.1
BRCA1	NM_001407582.1		c.*781C>T	3_prime_UTR	Exon 24 of 24	NP_001394511.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.*781C>T	3_prime_UTR	Exon 23 of 23	ENSP00000350283.3
BRCA1	ENST00000471181.7	TSL:1	c.*781C>T	3_prime_UTR	Exon 24 of 24	ENSP00000418960.2
BRCA1	ENST00000470026.6	TSL:1	c.*781C>T	3_prime_UTR	Exon 23 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes

AF:

0.00667

AC:

987

AN:

147994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00200

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000296

Gnomad OTH

AF:

0.00585

GnomAD2 exomes

AF:

0.00138

AC:

169

AN:

122496

AF XY:

0.000998

show subpopulations

Gnomad AFR exome

AF:

0.0247

Gnomad AMR exome

AF:

0.000569

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000129

Gnomad OTH exome

AF:

0.000529

GnomAD4 exome

AF:

0.000767

AC:

248

AN:

323394

Hom.:

Cov.:

AF XY:

0.000563

AC XY:

102

AN XY:

181080

show subpopulations

African (AFR)

AF:

0.0222

AC:

201

AN:

9060

American (AMR)

AF:

0.000648

AC:

AN:

26244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12330

East Asian (EAS)

AF:

0.00

AC:

AN:

14932

South Asian (SAS)

AF:

0.0000685

AC:

AN:

58406

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12228

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

1282

European-Non Finnish (NFE)

AF:

0.0000463

AC:

AN:

172874

Other (OTH)

AF:

0.000998

AC:

AN:

16038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00667

AC:

988

AN:

148092

Hom.:

Cov.:

AF XY:

0.00624

AC XY:

450

AN XY:

72068

show subpopulations

African (AFR)

AF:

0.0239

AC:

945

AN:

39572

American (AMR)

AF:

0.00199

AC:

AN:

14554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

4966

South Asian (SAS)

AF:

0.00

AC:

AN:

4708

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9954

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000296

AC:

AN:

67604

Other (OTH)

AF:

0.00579

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

123

164

205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00414

Hom.:

Bravo

AF:

0.00760

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Benign:2

Feb 17, 2014

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jan 12, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.03049 (African), derived from 1000 genomes (2012-04-30).

not specified

Benign:1

Dec 11, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Jun 15, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary breast ovarian cancer syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.3

(source)

DANN

Benign

0.62

PhyloP100

-0.073

Mutation Taster

=84/16

polymorphism

(source)

Splicing

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over