17-43093373-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4BP6

The NM_007294.4(BRCA1):c.2158G>A(p.Glu720Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,722 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. E720G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 0.574

Publications

26 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28328043).

BP6

Variant 17-43093373-C-T is Benign according to our data. Variant chr17-43093373-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 54479.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.2158G>A	p.Glu720Lys	missense_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.2158G>A	p.Glu720Lys	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000797

AC:

AN:

250954

AF XY:

0.00000737

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461722

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727158

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:

33474

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111978

Other (OTH)

AF:

0.00

AC:

AN:

60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), 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

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2

Nov 23, 2010

Sharing Clinical Reports Project (SCRP)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 19, 2011

Breast Cancer Information Core (BIC) (BRCA1)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Jan 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E720K variant (also known as c.2158G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 2158. The glutamic acid at codon 720 is replaced by lysine, an amino acid with similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). 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.

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).

not provided

Uncertain:1

Dec 21, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies suggest a neutral effect: reported with homology-directed repair activity comparable to wild type (PMID: 26689913); 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 2277G>A; This variant is associated with the following publications: (PMID: 32377563, 28152038, 29625052, 29884841, 15343273, 29684080, 30287823, 31853058, 36451132, 30702160, 26689913)

Hereditary breast ovarian cancer syndrome

Uncertain:1

Oct 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 720 of the BRCA1 protein (p.Glu720Lys). This variant is present in population databases (rs80356875, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 29625052). ClinVar contains an entry for this variant (Variation ID: 54479). 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. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 26689913). 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

0.11

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.;.;.;T

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.28

LIST_S2

Uncertain

0.88

D;D;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.28

T;T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.7

M;M;.;.;.

PhyloP100

0.57

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.2

D;D;D;D;.

Sift

Benign

0.054

T;D;T;T;.

Sift4G

Benign

0.24

T;T;T;T;.

Vest4

0.38

ClinPred

0.65

GERP RS

3.5

Varity_R

0.093

gMVP

0.13

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over