Genetic Variant BRCA1:p.Cys64Gly (chr17-43106478-A-C) – ACMG Classification: Pathogenic (15 pts)

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3PM2PP3PP5_Very_Strong

The NM_001407853.1(BRCA1):c.2T>G(p.Met1?) variant causes a start lost, splice region change. The variant allele was found at a frequency of 0.00000187 in 1,602,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004823687: Functional studies have reported that the variant impacts BRCA1 function in homology-directed repair, ubiquitin ligase, haploid cell proliferation and BARD1 binding assays and rescue of DNA damage sensitivity in BRCA1-deficient cells (PMID:8944023, 10635334, 11320250, 16403807, 20103620, 23867111, 25823446, 30209399)." and additional evidence is available in ClinVar. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRCA1
NM_001407853.1 start_lost, splice_region

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13U:2

Conservation

PhyloP100: 4.88

Publications

97 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

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV004823687: Functional studies have reported that the variant impacts BRCA1 function in homology-directed repair, ubiquitin ligase, haploid cell proliferation and BARD1 binding assays and rescue of DNA damage sensitivity in BRCA1-deficient cells (PMID: 8944023, 10635334, 11320250, 16403807, 20103620, 23867111, 25823446, 30209399).; SCV000075647: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20103620, 23161852). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 12915465, 26689913; internal data).; SCV000698899: Functional studies using HeLa cells confirmed this variant to be deleterious by using homology-directed recombination (HDR) and single-strand annealing (SSA) assays (Ransburgh_2010, Towler_2013).; SCV004847796: In vitro and in vivo functional studies support an impact on protein function (Findlay 2018, Wu 1996, Ruffner 2001, Yang 2003, Bouwman 2013, Towler 2013, Morris 2006, Lu 2015, Castilla 1994, Ransburgh 2010, Starita 2015, Maxwell 2017).; SCV000184711: Several independent DNA repair assays showed loss of function in p.C64G point mutants for BRCA1 ubiquitin ligase activity, homology directed recombination, functional complementation, and a high-throughput, genome editing, haploid cell survival assay (Scully R et al. Mol Cell, 1999 Dec;4:1093-9; Morris JR et al. Hum. Mol. Genet. 2006 Feb;15:599-606; Ransburgh DJ et al. Cancer Res. 2010 Feb;70:988-95; Towler WI et al. Hum. Mutat. 2013 Mar;34:439-45; Bouwman P et al. Cancer Discov. 2013 Oct;3:1142-55; Lu C et al. Nat Commun 2015 Dec;6:10086; Starita LM et al. Genetics. 2015 Jun;200:413-22; Findlay GM et al. Nature, 2018 10;562:217-222).; SCV000905209: Functional studies have reported that the variant impacts BRCA1 function in homology-directed repair, ubiquitin ligase, haploid cell proliferation and BARD1 binding assays and rescue of DNA damage sensitivity in BRCA1-deficient cells (PMID: 8944023, 10635334, 11320250, 16403807, 20103620, 23867111, 25823446, 30209399).; SCV000210068: Published functional studies demonstrate a damaging effect: defective homologous recombination and single-strand annealing repair, impaired BARD1 binding, and abrogation of ubiquitin ligase activity (Wu et al., 1996; Brzovic et al., 2003; Ransburgh et al., 2010; Bouwman et al., 2013; Towler et al., 2013; Lu et al., 2015)

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-43106478-A-C is Pathogenic according to our data. Variant chr17-43106478-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 17660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407853.1. 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.190T>G	p.Cys64Gly	missense	Exon 4 of 23	NP_009225.1	P38398-1
BRCA1	NM_001407581.1		c.190T>G	p.Cys64Gly	missense	Exon 4 of 24	NP_001394510.1	A0A2R8Y7V5
BRCA1	NM_001407582.1		c.190T>G	p.Cys64Gly	missense	Exon 4 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.190T>G	p.Cys64Gly	missense	Exon 4 of 23	ENSP00000350283.3	P38398-1
BRCA1	ENST00000471181.7	TSL:1	c.190T>G	p.Cys64Gly	missense	Exon 4 of 24	ENSP00000418960.2	P38398-7
BRCA1	ENST00000470026.6	TSL:1	c.190T>G	p.Cys64Gly	missense	Exon 4 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250804

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1450124

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

722022

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33216

American (AMR)

AF:

0.00

AC:

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26048

East Asian (EAS)

AF:

0.00

AC:

AN:

39538

South Asian (SAS)

AF:

0.00

AC:

AN:

85470

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102384

Other (OTH)

AF:

0.00

AC:

AN:

59940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 1 (7)

Hereditary breast ovarian cancer syndrome (3)

Hereditary cancer-predisposing syndrome (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Benign

0.67

DEOGEN2

Uncertain

0.48

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.6

PhyloP100

4.9

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.5

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.97

MutPred

0.99

Loss of stability (P = 0.0068)

MVP

1.0

MPC

0.45

ClinPred

0.77

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.86

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

3.0

SpliceAI score (max)

0.65

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.65

Position offset: -22

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