17-43093808-C-T

Position:

• chr17-43093808-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2
• Conservation: PhyloP100: -0.0160

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.1723G>A	p.Glu575Lys	missense_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.1723G>A	p.Glu575Lys	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250624 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135504

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: 29 AN: 1461170 Hom.: 0 Cov.: 34 AF XY: 0.0000193 AC XY: 14 AN XY: 726922

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.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 05, 2023	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign: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	May 04, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 22, 2023	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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 27, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2019	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

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 28, 2021

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	12
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	N
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.7	M;M;.;.;.;.;.
PrimateAI	Benign	0.31	T
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	D
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

Other links and lift over

dbSNP: rs397508902; hg19: chr17-41245825; COSMIC: COSV58798098; COSMIC: COSV58798098;