Genetic Variant BRCA1:p.Met1775Arg (chr17-43051071-A-C) – ACMG Classification: Pathogenic (20 pts)

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_007294.4(BRCA1):c.5324T>G(p.Met1775Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000210213: Published functional studies demonstrate a damaging effect: abolishes BRCA1 activity, including double strand break repair, transcription, and binding functions (Monteiro 1996, Kawai 2002, Williams 2003, Varma 2005, Towler 2013); SCV000296388: "In addition, experimental studies showed this variant has deleterious effect on various BRCA1 protein functions (PMIDs: 23161852 (2013), 20516115 (2010), 17308087 (2007), 16786532 (2006), 15689452 (2005), 15133502 (2004))."; SCV000591612: Several functional studies have concluded that this variant has a deleterious effect on BRCA1 protein function. The mutation has been shown to inhibit the interaction of BRCA1 with the DNA helicase BACH1 (Clapperton 2004, Shiozaki 2004) and with the transcriptional corepressor CtIP (Varma 2005), and yeast and mammalian cell-based assays have demonstrated that the variant impairs transcription activation (Monteiro 1996, Phelan 2005, Tischkowitz 2008). One study utilized a proteolytic sensitivity assay which indicated that the variant results in a folding defect in the BRCT domains, and thus destabilization of this domain (Williams 2003).; SCV002050101: Functional analyses of the variant protein show reduced protein stability and a severe impact on BRCA1 function (Caligo 2009, Fernandes 2019, Lee 2010, Towler 2013, Williams 2003).; SCV000186351: "One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562(7726):217-222). Numerous other functional studies have also found this variant to be deleterious (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-883; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee M et al. Hum. Mutat. 2012 Jan;33:22-8; Towler WI et al. Hum Mutat. 2013 Mar;34:439-45; Petitalot A et al. Mol Cancer Res. 2019 01;17:54-69)."; SCV000537680: Functional studies have shown that this variant impacts BRCA1 function in homology-directed DNA repair, transcription activation, haploid cell proliferation, sensitivity to cisplatin, PARP inhibitors and protease, and protein-protein binding assays (PMID:8942979, 9738006, 11301010, 12427738, 15689452, 23161852, 30209399, 30257991, 30765603, 32546644).; SCV000076944: Experimental studies have shown that this missense change affects BRCA1 function (PMID:12400015, 14534301, 19493677, 20516115, 23161852).; SCV000699236: Functional studies demonstrated the variant to impair homology directed repair, single strand annealing, phosphopeptide-binding and transcriptional activity of BRCA1 further supporting a deleterious impact.; SCV004848275: In vitro functional studies support an impact on protein function (Kawai 2002 PMID:12400015, Caligo 2009 PMID:18680205, Lee 2010 PMID:20516115, Findlay 2018 PMID:30209399); SCV005425631: Functional studies have shown that this variant impacts BRCA1 function in homology-directed DNA repair, transcription activation, haploid cell proliferation and protease sensitivity and protein-protein binding assays (PMID:8942979, 9738006, 11301010, 12427738, 15689452, 23161852, 30209399).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1775L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:23U:1

Conservation

PhyloP100: 5.03

Publications

153 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: Pathogenic. The variant received 20 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000210213: Published functional studies demonstrate a damaging effect: abolishes BRCA1 activity, including double strand break repair, transcription, and binding functions (Monteiro 1996, Kawai 2002, Williams 2003, Varma 2005, Towler 2013); SCV000296388: "In addition, experimental studies showed this variant has deleterious effect on various BRCA1 protein functions (PMIDs: 23161852 (2013), 20516115 (2010), 17308087 (2007), 16786532 (2006), 15689452 (2005), 15133502 (2004))."; SCV000591612: Several functional studies have concluded that this variant has a deleterious effect on BRCA1 protein function. The mutation has been shown to inhibit the interaction of BRCA1 with the DNA helicase BACH1 (Clapperton 2004, Shiozaki 2004) and with the transcriptional corepressor CtIP (Varma 2005), and yeast and mammalian cell-based assays have demonstrated that the variant impairs transcription activation (Monteiro 1996, Phelan 2005, Tischkowitz 2008). One study utilized a proteolytic sensitivity assay which indicated that the variant results in a folding defect in the BRCT domains, and thus destabilization of this domain (Williams 2003).; SCV002050101: Functional analyses of the variant protein show reduced protein stability and a severe impact on BRCA1 function (Caligo 2009, Fernandes 2019, Lee 2010, Towler 2013, Williams 2003).; SCV000186351: "One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562(7726):217-222). Numerous other functional studies have also found this variant to be deleterious (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-883; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee M et al. Hum. Mutat. 2012 Jan;33:22-8; Towler WI et al. Hum Mutat. 2013 Mar;34:439-45; Petitalot A et al. Mol Cancer Res. 2019 01;17:54-69)."; SCV000537680: Functional studies have shown that this variant impacts BRCA1 function in homology-directed DNA repair, transcription activation, haploid cell proliferation, sensitivity to cisplatin, PARP inhibitors and protease, and protein-protein binding assays (PMID: 8942979, 9738006, 11301010, 12427738, 15689452, 23161852, 30209399, 30257991, 30765603, 32546644).; SCV000076944: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 12400015, 14534301, 19493677, 20516115, 23161852).; SCV000699236: Functional studies demonstrated the variant to impair homology directed repair, single strand annealing, phosphopeptide-binding and transcriptional activity of BRCA1 further supporting a deleterious impact.; SCV004848275: In vitro functional studies support an impact on protein function (Kawai 2002 PMID: 12400015, Caligo 2009 PMID: 18680205, Lee 2010 PMID: 20516115, Findlay 2018 PMID: 30209399); SCV005425631: Functional studies have shown that this variant impacts BRCA1 function in homology-directed DNA repair, transcription activation, haploid cell proliferation and protease sensitivity and protein-protein binding assays (PMID: 8942979, 9738006, 11301010, 12427738, 15689452, 23161852, 30209399).

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 18 benign, 81 uncertain in NM_007294.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-43051071-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 825652.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

PP5

Variant 17-43051071-A-C is Pathogenic according to our data. Variant chr17-43051071-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 17694.Status of the report is reviewed_by_expert_panel, 3 stars.

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.5324T>G	p.Met1775Arg	missense	Exon 20 of 23	NP_009225.1	P38398-1
BRCA1	NM_001407581.1		c.5390T>G	p.Met1797Arg	missense	Exon 21 of 24	NP_001394510.1	A0A2R8Y7V5
BRCA1	NM_001407582.1		c.5390T>G	p.Met1797Arg	missense	Exon 21 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.5324T>G	p.Met1775Arg	missense	Exon 20 of 23	ENSP00000350283.3	P38398-1
BRCA1	ENST00000471181.7	TSL:1	c.5387T>G	p.Met1796Arg	missense	Exon 21 of 24	ENSP00000418960.2	P38398-7
BRCA1	ENST00000470026.6	TSL:1	c.5324T>G	p.Met1775Arg	missense	Exon 20 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000119

AC:

AN:

251394

AF XY:

0.0000147

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:

0.00000274

AC:

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111932

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 1 (10)

Hereditary breast ovarian cancer syndrome (5)

not provided (4)

Hereditary cancer-predisposing syndrome (2)

BRCA1-related cancer predisposition (1)

BRCA1-related disorder (1)

Breast and/or ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.3

PhyloP100

5.0

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.96

MPC

0.55

ClinPred

0.94

GERP RS

5.2

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.95

gMVP

0.87

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over