rs80357091

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_007294.4(BRCA1):c.259T>G(p.Leu87Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,662 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: 0.0000021 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1O:1

Conservation

PhyloP100: 0.239

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:

BRCA1 (HGNC:):

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36205995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.259T>G	p.Leu87Val	missense_variant	5/23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.259T>G	p.Leu87Val	missense_variant	5/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251246

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461662

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.000223

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2017	This variant is denoted BRCA1 c.259T>G at the cDNA level, p.Leu87Val (L87V) at the protein level, and results in the change of a Leucine to a Valine (TTG>GTG). Using alternate nomenclature, this variant would be defined as BRCA1 378T>G. This variant has been observed in individuals with personal and/or family history of breast and/or ovarian cancer (Shattuck-Eidens 1997, Brzovic 2001). In functional assays, BRCA1 Leu87Val did not inhibit BARD1 protein interaction and was able to rescue homology-directed repair comparable to wild type (Morris 2006, Starita 2015). However, results of the variant's effect on ligase activity varied, with Morris et al. (2006) observing no impact on E3 ubiquitin ligase activity while Starita et al. (2015) showed reduced E3 ligase function compared to wild type. Of note, this variant was not associated with splicing defects or exon skipping (Raponi 2011). BRCA1 Leu87Val was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Leu87Val occurs at a position that is conserved across species and is located in the RING domain and a region known to interact with multiple proteins (Borg 2010, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Leu87Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 08, 2016	Variant summary: The BRCA1 c.259T>G (p.Leu87Val) variant involves the alteration of a non-conserved nucleotide located in the antiparallel alpha-helices flanking the central RING domain thought to be critical for the proper association of the BRCA1 and BARD1 protein (Brzovic_Nat Struct Biol_2001). 2/4 in silico tools predict a benign outcome for this substitution. The variant is absent in 121322 control chromosomes and to our knowledge, it was not reported in affected patients with strong evidence for pathogenicity either at the time of this classification. A functional study demonstrated the variant to retain homology directed repair activity, the BARD1 and UbcH5a binding of BRCA1, however, conflicting evidence has been reported on its effect on the E3 ubiquitin ligase activity (Starita_Genetics_2015 and Morris_HumMolGenet_2006). Due to the lack of clinical information, this variant is classified as variant of uncertain significance. -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 19, 2016	- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 09, 2023

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 87 of the BRCA1 protein (p.Leu87Val). This variant is present in population databases (rs80357091, gnomAD 0.02%). This missense change has been observed in individual(s) with BRCA1-related conditions (PMID: 9333265). This variant is also known as c.378T>G. ClinVar contains an entry for this variant (Variation ID: 54614). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 16403807, 25823446, 30209399). 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

May 20, 2021

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

Benign

0.19

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

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

Eigen

Benign

0.031

Eigen_PC

Benign

-0.099

FATHMM_MKL

Benign

0.40

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.36

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

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.5

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

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.31

N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N;N;.

REVEL

Uncertain

0.62

Sift

Uncertain

0.027

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

Sift4G

Benign

0.53

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

Polyphen

0.30, 0.99, 0.98

.;B;.;.;.;D;.;.;.;.;D;.;.;.;.;.;.;.

Vest4

0.56

MutPred

0.37

Gain of methylation at K88 (P = 0.0444);Gain of methylation at K88 (P = 0.0444);Gain of methylation at K88 (P = 0.0444);Gain of methylation at K88 (P = 0.0444);.;Gain of methylation at K88 (P = 0.0444);.;Gain of methylation at K88 (P = 0.0444);.;.;Gain of methylation at K88 (P = 0.0444);Gain of methylation at K88 (P = 0.0444);Gain of methylation at K88 (P = 0.0444);.;Gain of methylation at K88 (P = 0.0444);Gain of methylation at K88 (P = 0.0444);.;.;

MVP

0.94

MPC

0.42

ClinPred

0.72

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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