17-43093808-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6

The NM_007294.4(BRCA1):c.1723G>A(p.Glu575Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,170 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).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: -0.0160

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.38743874).

BP6

Variant 17-43093808-C-T is Benign according to our data. Variant chr17-43093808-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54334.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.1723G>A	p.Glu575Lys	missense_variant	Exon 10 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.1723G>A	p.Glu575Lys	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250624

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135504

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461170

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726922

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000929

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:3

Jul 05, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 05, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

a variant of uncertain significance was detected in the BRCA1 gene. The p.E575K variant (also known as c.1723G>A), located in coding region of the BRCA1 gene, results from a G to A substitution at nucleotide position 1723. The glutamic acid at codon 575 is replaced by lysine, an amino acid with similar properties. The alteration did not segregate with disease in one family (PMID 14647443). In another study, this variant was shown to have no effect on alternate splicing using minigene splicing assay (PMID 18273839). An additional paper reported this alteration in 1/645 women with breast cancer from Shanghai, China (PMID 14973102). Of note, this alteration is also designated as 1842G>A in published literature. This amino acid position is not well conserved in available vertebrate species. ClinVar has an entry for this variant with 6 submissions all of which classify it as of uncertain significance, 2 stars, no conflicts. In-silico prediction for this alteration shows Pathogenic computational verdict based on 8 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, LIST-S2, M-CAP, MVP, MutationAssessor and SIFT vs 4 benign predictions from EIGEN, FATHMM-MKL, MutationTaster and PrimateAI. Therefore, this variant is classified as on uncertain significance. Pathogenic/Likely pathogenic BRCA1 variants cause hereditary breast/ovarian cancer syndrome (HBOC). -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Aug 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E575K variant (also known as c.1723G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1723. The glutamic acid at codon 575 is replaced by lysine, an amino acid with similar properties. In one study, lymphoblast cell lines with this alteration demonstrated impaired fidelity of double strand breakage repair by DNA end-joining compared to the normal control cell line. However, the alteration did not segregate with disease in one family (Coupier I et al. Oncogene 2004 Jan; 23(4):914-9). In another study, this variant was shown to have no effect on alternate splicing using minigene splicing assay (Anczukow O et al. Genes Chromosomes Cancer. 2008; 47:418-26). An additional paper reported this alteration in 1/645 women with breast cancer from Shanghai, China (Suter NM et al, Cancer Epidemiol. Biomarkers Prev. 2004 Feb; 13(2):181-9), and in a study of 1854 high-risk breast/ovarian cancer families in Italy, this alteration was detected in 1 family (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71). Of note, this alteration is also designated as 1842G>A in published literature. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

May 04, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 575 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). One functional study observed partial activity in an ex vivo repair assay of an extrachromosomal plasmid (PMID: 14647443). This variant has been reported in at least two unrelated individuals affected with breast cancer (PMID: 14647443, 14973102) and two suspected hereditary breast and ovarian cancer families (PMID: 27062684, 31954625). However, this variant did not segregate completely with breast cancer affected members of a family (PMID: 14647443). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000164). This variant has been identified in 5/250624 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. -

not provided

Uncertain:2

Apr 27, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.1723G>A (p.Glu575Lys) variant has been reported in the published literature in high-risk breast and/or ovarian cancer families (PMIDs: 34981296 (2022), 31954625 (2020), 31825140 (2019), 27062684 (2016), 18273839 (2008), 14647443 (2004), 14973102 (2004)), as well as in an individual with breast cancer in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)). This variant was also reported to be damaging to DNA break repair activity in a cell-based study (PMID: 14647443 (2004)). The frequency of this variant in the general population, 0.00002 (5/250624 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Dec 03, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal and/or family history of breast and/or ovarian cancer; however, did not co-segregate with breast cancer in one family (Coupier 2004, Suter 2004, Anczukow 2008); Published functional studies demonstrate a damaging effect: impaired DNA break repair activity (Coupier 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 1842G>A; This variant is associated with the following publications: (PMID: 25348012, 14647443, 20858050, 14973102, 23893897, 26269718, 18273839, 31825140) -

BRCA1-related cancer predisposition

Uncertain:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S

Uncertain:1

Oct 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

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

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.39

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

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.7

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

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.0

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

REVEL

Uncertain

0.62

Sift

Benign

0.039

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

Sift4G

Uncertain

0.045

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

Polyphen

0.76

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

Vest4

0.36

MutPred

0.33

Gain of ubiquitination at E575 (P = 0.0117);Gain of ubiquitination at E575 (P = 0.0117);.;Gain of ubiquitination at E575 (P = 0.0117);.;Gain of ubiquitination at E575 (P = 0.0117);.;

MVP

0.93

MPC

0.29

ClinPred

0.75

GERP RS

3.9

Varity_R

0.093

gMVP

0.18

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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