chr17-43094720-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BA1BP1_StrongBS3

This summary comes from the ClinGen Evidence Repository: The c.811G>A variant in BRCA1 is a missense variant predicted to cause substitution of valine by methionine at amino acid 271 (p.Val271Met). The highest non-founder population filter allele frequency in gnomAD v4.1 (read depth ≥20) is 0.001630 in the East Asian population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using SpliceAI (score 0.03, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID:32546644) (BS3 met).In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP1_Strong, BS3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA003905/MONDO:0700268/092

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

BRCA1
NM_001407966.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:2B:19

Conservation

PhyloP100: 0.213

Publications

37 publications found

Variant links:

COSMIC-nc: COSV58800388

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 -16 ACMG points.

BP1

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407966.1. 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.811G>A	p.Val271Met	missense	Exon 10 of 23	NP_009225.1	P38398-1
BRCA1	NM_001407966.1		c.-78G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 15	NP_001394895.1	C9IZW4
BRCA1	NM_001407967.1		c.-78G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 15	NP_001394896.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCA1	ENST00000497488.2	TSL:1	c.-78G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 15	ENSP00000418986.2	C9IZW4
BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.811G>A	p.Val271Met	missense	Exon 10 of 23	ENSP00000350283.3	P38398-1
BRCA1	ENST00000471181.7	TSL:1	c.811G>A	p.Val271Met	missense	Exon 10 of 24	ENSP00000418960.2	P38398-7

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000919

AC:

AN:

250228

AF XY:

0.0000961

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00125

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000562

AC:

AN:

1459460

Hom.:

Cov.:

AF XY:

0.0000648

AC XY:

AN XY:

725678

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33358

American (AMR)

AF:

0.00

AC:

AN:

44530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00207

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

86140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110294

Other (OTH)

AF:

0.00

AC:

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.0000394

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41546

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000198

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000988

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 1 (5)

not specified (5)

Hereditary cancer-predisposing syndrome (4)

BRCA1-related cancer predisposition (2)

Hereditary breast ovarian cancer syndrome (2)

Familial cancer of breast (1)

Malignant tumor of breast (1)

Malignant tumor of pancreas (1)

Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.041

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.8

PhyloP100

0.21

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.56

Sift

Benign

0.14

Sift4G

Benign

0.14

Polyphen

0.88

Vest4

0.44

MVP

0.84

MPC

0.32

ClinPred

0.20

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.046

gMVP

0.19

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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