17-43063909-C-T

Position:

chr17-43063909-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_007294.4(BRCA1):c.5117G>A(p.Gly1706Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,942 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1706A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:13U:1O:1

Conservation

PhyloP100: 4.86

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 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 chr17-43063910-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 267219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.886

PP5

Variant 17-43063909-C-T is Pathogenic according to our data. Variant chr17-43063909-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37638.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063909-C-T is described in Lovd as [Pathogenic]. Variant chr17-43063909-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.5117G>A	p.Gly1706Glu	missense_variant	17/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.5117G>A	p.Gly1706Glu	missense_variant	17/23	1	NM_007294.4	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000251

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Uncertain:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:5Uncertain:1Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 16, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 11, 2023	This missense variant replaces glycine with glutamic acid at codon 1706 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in transcription activation assays (PMID: 17308087, 20516115, 27742776, 28781887), homology-directed repair assay (PMID: 23867111) and in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in at least nine individuals affected with breast and/or ovarian cancer (PMID: 11979449, 17262179, 20727672, 24240112, 25682074, 29928469) and as a recurrent mutation in the Spanish population (PMID: 23199084). This variant has been identified in 1/31406 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 -
Pathogenic, criteria provided, single submitter	research	Institute of Genomics, University of Tartu	-	- -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1706 of the BRCA1 protein (p.Gly1706Glu). This variant is present in population databases (rs80356860, gnomAD 0.007%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10755399, 11979449, 12385650, 20727672, 29446198). This variant is also known as 5236G>A. ClinVar contains an entry for this variant (Variation ID: 37638). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 23867111, 28781887, 30209399). This variant disrupts the p.Gly1706 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17262179, 22144684, 25948282, 27616075, 30209399, 30458859). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 17, 2015	The p.Gly1727Glu variant in BRCA1 has been reported in at least 9 individuals wi th breast cancer, segregated with disease in 2 affected relatives from 1 family (Osorio 2000, Iyevleva 2010, Breast Cancer Information Core (BIC) database), and was absent from large population studies. In vitro functional studies provide s ome evidence that the missense variant may impact protein function (Bouwman 2013 ). However, these types of assays may not accurately represent biological functi on. Computational prediction tools and conservation analysis do not provide stro ng support for or against an impact to the protein. In summary, although additio nal studies are required to fully establish its clinical significance, the p.Gly 1727Glu variant is likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 21, 2021	Variant summary: BRCA1 c.5117G>A (p.Gly1706Glu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251342 control chromosomes. c.5117G>A has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Several publications reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of Homology Directed Repair (HDR) activity (example, Findlay_2018). Six clinical diagnostic laboratories, one consortium (CIMBA) and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=4) to include the expert panel / likely pathogenic(n=4). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2020	Published functional studies demonstrate a damaging effect: decreased transcription activation, abnormal protease sensitivity, binding specificity, and phosphopeptide binding, sensitivity to cisplatin, and absent ability to support growth in BRCA1-deficient mouse embryonic stem cells (Bouwman 2013, Thouvenot 2016, Woods 2016, Fernandes 2019); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in multiple individuals with breast and/or ovarian cancer, and segregated with disease in at least one family (Osorio 2002, Esteban-Cardenosa 2004, Ivevleva 2010); Also known as 5236G>A; This variant is associated with the following publications: (PMID: 17305420, 20727672, 15235020, 15172985, 26071757, 23867111, 30209399, 27272900, 30765603, 17924331, 26780556, 14684619, 17308087, 21447777, 11979449, 12955716, 10755399, 20516115, 21990134, 28781887, 29446198, 32318955, 32123317) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 10, 2020	The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 20, 2021	This missense variant replaces glycine with glutamic acid at codon 1706 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in transcription activation assays (PMID: 17308087, 20516115, 27742776, 28781887), homology-directed repair assay (PMID: 23867111) and in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in at least nine individuals affected with breast and/or ovarian cancer (PMID: 11979449, 17262179, 20727672, 24240112, 25682074, 29928469) and as a recurrent mutation in the Spanish population (PMID: 23199084). This variant has been identified in 1/31406 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 29, 2024	The p.G1706E variant (also known as c.5117G>A), located in coding exon 16 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5117. The glycine at codon 1706 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in numerous breast and ovarian cancer families and has been described as a Spanish founder mutation that segregates with disease in multiple, affected family members (Osorio A et al. Br J Cancer. 2000 Apr;82(7):1266-70; Diez O et al. Hum Mutat. 2003 Oct;22(4):301-12; Janavicius R. EPMA J. 2010 Sep;1(3):397-412; Iyevleva AG et al. Cancer Lett. 2010 Dec 8;298(2):258-63; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473). Functional assays have also shown this alteration to have a deleterious biological effect (Carvalho MA et al. Cancer Res. 2007 Feb 15;67(4):1494-501; Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90; Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55; Woods NT et al. npg Genomic Medicine 2016: 1:16001; Findlay GM et al. Nature, 2018 10;562:217-222). This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Easton D et al. Am J Hum Genet. 2007;81:873-883; Iversen ES Jr et al. Cancer Epidemiol Biomarkers Prev. 2011 Jun;20(6):1078-88; Lindor NM et al. Hum Mutat. 2012 Jan;33(1):8-21). Further, internal structural analysis suggests this alteration is likely pathogenic due to a highly increased global energy change as well as a higher local energy increase compared to other pathogenic variants within close proximity (Ambry Internal Data; Birrane G et al. Biochemistry, 2007 Jul;46:7706-12; Williams RS et al. Cell, 2009 Oct;139:87-99). Of note, this alteration is also referred to as 5236G>A in published literature. 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. -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

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

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.89

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

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

3.2

.;M;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-6.0

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

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.88, 1.0

.;P;.;.;.;D;.;.;.;D;.

Vest4

0.99

MVP

0.98

MPC

0.51

ClinPred

0.99

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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