17-43047678-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_007294.4(BRCA1):c.5432A>G(p.Gln1811Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1811H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:2

Conservation

PhyloP100: 4.16

Publications

20 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: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 17 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 chr17-43047678-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 868483.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.804

PP5

Variant 17-43047678-T-C is Pathogenic according to our data. Variant chr17-43047678-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 55578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.5432A>G	p.Gln1811Arg	missense_variant	Exon 22 of 23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.5432A>G	p.Gln1811Arg	missense_variant	Exon 22 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

Cov.:

Alfa

AF:

0.0000427

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:2Uncertain:2

Feb 28, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 10, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 30, 1998

Breast Cancer Information Core (BIC) (BRCA1)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 05, 2012

Sharing Clinical Reports Project (SCRP)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Dec 04, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Q1811R variant (also known as c.5432A>G), located in coding exon 21 of the BRCA1 gene, results from an A to G substitution at nucleotide position 5432. The glutamine at codon 1811 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in a Brazilian pancreatic cancer cohort (Rodrigues LM. Sci Rep. 2024 Sep;14(1):21083). Multiple functional assays report this variant as having a deleterious impact (Findlay GM et al. Nature, 2018 10;562:217-222; Carvalho MA et al. Cancer Biol. Ther.;1:502-8; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Petitalot A. Mol Cancer Res. 2019 Jan;17(1):54-69). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Oct 15, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glutamine with arginine at codon 1811 of the BRCA1 protein. Computational predictions suggest that this variant may have deleterious impact on protein structure and function (PMID: 27666373, 37733863). Functional studies have reported that this variant impacts BRCA1 functions in transcription activation, phosphopeptide binding, protease sensitivity, homology-directed DNA repair and a haploid cell proliferation assay (PMID: 12496477, 20516115, 30209399, 30257991, 30765603). This variant has been detected in three individuals affected with breast cancer (PMID: 38640836, 38709234; Color internal data). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on personal and family history of 0.983 from log(LR)=-0.007226169 for three carriers (PMID: 31853058). A different missense variant at this codon, c.5432A>C (p.Gln1811Pro), has been reported as likely disease-causing in ClinVar (variation ID: 868483). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

BRCA1-related cancer predisposition

Pathogenic:1

Sep 12, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5432A>G (p.Gln1811Arg) variant in the BRCA1 gene replaces glutamine with arginine at codon 1811 in exon 22. This variant has been identified in three individuals in a large hereditary cancer multigene panel testing cohort study (PMID: 31853058). Experimental studies have shown that this variant may lead to reduced transcription activity, and defective homology-directed DNA repair and localization (PMID: 12496477, 28781887, 30209399, 30257991, 30765603, 35196514). This variant is absent in the general population database gnomAD. Computational prediction algortihms suggest a deleterious effect (REVEL score 0.70). This variant has been reported in ClinVar as likely pathogenic by multiple submitters (Variation ID: 55578). Therefore, the c.5432A>G (p.Gln1811Arg) variant in the BRCA1 gene is classified as likely pathogenic. -

not provided

Pathogenic:1

Oct 25, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies support a damaging effect: Reduced binding activity and specificity, and severely defective transcriptional activity, homology directed DNA repair, nuclear localization, and folding, and was classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (PMID: 20516115, 28781887, 30209399, 30257991, 35665744, 35196514); Identified in individuals referred for multi-gene panel testing with personal or family history of cancer (PMID: 31853058); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5551A>G; This variant is associated with the following publications: (PMID: 10946236, 30257991, 12496477, 15235020, 15172985, 14534301, 28781887, 30209399, 17305420, 20516115, 25348405, 37718511, 30765603, 35665744, 29884841, 31086113, 35196514, 31853058) -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Oct 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1811 of the BRCA1 protein (p.Gln1811Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 10923033, 21520333). ClinVar contains an entry for this variant (Variation ID: 55578). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 12496477, 20516115, 28781887, 30209399, 30765603). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

.;T;.;T;T;T;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.27

PhyloP100

4.2

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.1

D;N;.;.;.;.;N;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0020

D;D;.;.;.;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D

Polyphen

1.0, 0.99

.;D;.;.;.;D;.;.

Vest4

0.72

MVP

0.96

MPC

0.41

ClinPred

0.99

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.74

gMVP

0.66

Mutation Taster

=63/37

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over