17-43115774-T-C

Position:

chr17-43115774-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_007294.4(BRCA1):c.86A>G(p.Glu29Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,172 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E29A) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1O:2

Conservation

PhyloP100: 3.52

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 Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 8 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.86A>G	p.Glu29Gly	missense_variant	3/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.86A>G	p.Glu29Gly	missense_variant	3/23	1	NM_007294.4	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151976

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

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250508

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135392

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461196

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726860

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151976

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74232

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

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Other:1

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	- -

not provided

Uncertain:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 07-04-2016 by Lab Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 16, 2020	The BRCA1 c.86A>G; p.Glu29Gly variant (rs773841328), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 231722). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamic acid at codon 29 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, in vitro functional analyses demonstrate little effect on homology directed repair activity (Starita 2018). Due to limited information, the clinical significance of the p.Glu29Gly variant is uncertain at this time. References: Starita LM et al. A Multiplex Homology-Directed DNA Repair Assay Reveals the Impact of More Than 1,000 BRCA1 Missense Substitution Variants on Protein Function. Am J Hum Genet. 2018;103(4):498-508. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 07, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 29 of the BRCA1 protein (p.Glu29Gly). This variant is present in population databases (rs773841328, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 231722). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) 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: 30219179). 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. -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

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

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

D;T;T;T;D;D;T;D;D;D;T;D;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.81

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

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

1.5

L;L;L;L;L;.;.;.;.;.;.;.;.

MutationTaster

Benign

0.99

D;D;D;D;D;D;D;D;D;D;N;N;N;N

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.6

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

REVEL

Pathogenic

0.73

Sift

Uncertain

0.015

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

Sift4G

Uncertain

0.0060

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

Polyphen

0.99, 1.0

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

Vest4

0.65

MutPred

0.66

Loss of stability (P = 0.0484);Loss of stability (P = 0.0484);Loss of stability (P = 0.0484);Loss of stability (P = 0.0484);Loss of stability (P = 0.0484);Loss of stability (P = 0.0484);Loss of stability (P = 0.0484);Loss of stability (P = 0.0484);Loss of stability (P = 0.0484);Loss of stability (P = 0.0484);Loss of stability (P = 0.0484);Loss of stability (P = 0.0484);Loss of stability (P = 0.0484);

MVP

0.95

MPC

0.48

ClinPred

0.88

GERP RS

6.0

Varity_R

0.39

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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

Other links and lift over