chr17-43094198-C-G

Position:

chr17-43094198-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_007294.4(BRCA1):c.1333G>C(p.Glu445Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E445G) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:3

Conservation

PhyloP100: 0.541

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 Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25946692).

BP6

Variant 17-43094198-C-G is Benign according to our data. Variant chr17-43094198-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54203.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}. Variant chr17-43094198-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.1333G>C	p.Glu445Gln	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.1333G>C	p.Glu445Gln	missense_variant	10/23	1	NM_007294.4	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250918

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461774

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727186

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:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:3Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Uncertain significance, no assertion criteria provided	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 05, 2023	The p.E445Q variant (also known as c.1333G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 1333. The glutamic acid at codon 445 is replaced by glutamine, an amino acid with highly similar properties. One study showed that this variant performed similarly to the wildtype in a homology-directed repair assay (Lu C et al. Nat Commun. 2015 Dec;6:10086). This alteration has been reported as a variant of unknown significance some published studies; however, no clinical or other supporting information is provided (Judkins T et al. Cancer Res. 2005 Nov;65:10096-103; Coulet F et al. Genet Test Mol Biomarkers. 2010 Oct;14:677-90). This variant has also been reported in 1/1854 hereditary breast and/or ovarian cancer families (Azzollini J Eur. J. Intern. Med. 2016 Jul;32:65-71). This amino acid position is poorly conserved in available vertebrate species. In addition, in silico analysis showed benign computational verdict based on 8 benign predictions from BayesDel_addAF, DANN, EIGEN, FATHMM-MKL, MVP and 3 more vs 5 pathogenic predictions from DEOGEN2, LIST-S2, M-CAP, MutationAssessor and SIFT and the position is not strongly conserved (GERP++ rejected substitutions = 0.761 is less than 5.5). This variant has an entry in ClinVar with 8 submissions all of which list it as uncertain significance. Therefore, this variant is classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 23, 2023	This missense variant replaces glutamic acid with glutamine at codon 445 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has been reported that this variant does not impact BRCA1 function in a homology-directed repair assay (PMID: 26689913). This variant has been reported in at least four individuals affected with breast cancer and in suspected hereditary breast and ovarian cancer families (PMID: 26689913, 27062684, 29409476, 30613976, 31409081), and in a breast cancer case-control meta-analysis in 2/53459 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000141). This variant also has been reported in an individual affected with oligodendroglioma (PMID: 29625052) and in two individuals affected with Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (PMID: 29684080). This variant has been identified in 7/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	BS1(Supporting)+BS3(Strong)+BP1(Strong)+BP5(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 03, 2023	This missense variant replaces glutamic acid with glutamine at codon 445 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has been reported that this variant does not impact BRCA1 function in a homology-directed repair assay (PMID: 26689913). This variant has been reported in at least four individuals affected with breast cancer and in suspected hereditary breast and ovarian cancer families (PMID: 26689913, 27062684, 294094760, 30613976, 31409081), and in a breast cancer case-control meta-analysis in 2/53459 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000141). This variant also has been reported in an individual affected with oligodendroglioma (PMID: 29625052) and in two individuals affected with Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (PMID: 29684080). This variant has been identified in 7/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 30, 2023	The p.E445Q variant (also known as c.1333G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 1333. The glutamic acid at codon 445 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Abdel-Razeq H et al. BMC Cancer, 2018 02;18:152; Machackova E et al. Klin Onkol, 2019;32:51-71; Rizzolo P et al. Int J Cancer, 2019 Jul;145:390-400; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). This alteration has also been reported in a low grade glioma patient from from The Cancer Genome Atlas (TCGA) (Huang KL et al. Cell, 2018 04;173:355-370.e14). In another study, this variant was reported in 0/60,466 breast cancer cases and in 2/53,461 healthy controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In addition, this alteration was functional in a homology directed DNA repair (HDR) assay (Lu C et al. Nat Commun, 2015 Dec;6:10086). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 24, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 1452G>C; This variant is associated with the following publications: (PMID: 20858050, 31409081, 16518693, 16267036, 23704879, 15385441, 26689913, 27062684, 29409476, 29684080, 28529006, 32546644, 33471991, 20104584, 32377563, 20215511, 10426999, 9788437, 9582019, 9926942, 15343273, 31853058, 29625052, 34981296, 30613976, 34326862, 36451132, 35402282) -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 15, 2023	Variant summary: BRCA1 c.1333G>C (p.Glu445Gln) results in a conservative amino acid change located in the BRCA1, serine-rich domain (IPR025994) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250918 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1333G>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (example: Abdel-Razeq_2018, Azzollini_2016, Coulet_2010, Judkins_2005, Machackova_2019, Rizzolo_2019). At-least one report of this variant co-occurring with a pathogenic variant (c.2062C>T, p.Gln688*) in the PTCH1 gene as an alternate molecular basis of disease in an individual with Gorlin syndrome has been reported (Paulo_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had comparable homology-directed repair (HDR) activity to the wild type (example: Lu_2015 and Bouwman_2020). Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 445 of the BRCA1 protein (p.Glu445Gln). This variant is present in population databases (rs80356915, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, male breast cancer, and/or ovarian cancer (PMID: 26689913, 27062684, 29409476, 29625052, 30613976, 34981296). ClinVar contains an entry for this variant (Variation ID: 54203). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 26689913, 32546644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.63

D;.;.;.;T;T;.;.;T

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.14

LIST_S2

Pathogenic

0.98

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

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.26

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

3.5

H;H;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-2.3

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

REVEL

Uncertain

0.53

Sift

Uncertain

0.016

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

Sift4G

Uncertain

0.014

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

Polyphen

1.0

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

Vest4

0.46

MutPred

0.42

Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);.;Gain of helix (P = 6e-04);.;Gain of helix (P = 6e-04);.;.;Gain of helix (P = 6e-04);

MVP

0.85

MPC

0.44

ClinPred

0.17

GERP RS

0.76

Varity_R

0.12

gMVP

0.12

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

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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