rs80357227

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_007294.4(BRCA1):c.5216A>T(p.Asp1739Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1739G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 4.74

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-43057113-T-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

PP5

Variant 17-43057113-T-A is Pathogenic according to our data. Variant chr17-43057113-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43057113-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.5216A>T	p.Asp1739Val	missense_variant	Exon 19 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.5216A>T	p.Asp1739Val	missense_variant	Exon 19 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 11, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data is high quality. Conflicting predictions of the effect on the protein. Located in potentially critical domain of the protein. Found in at least one patient with expected phenotype for this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Apr 21, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA1 c.5216A>T at the cDNA level, p.Asp1739Val (D1739V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). Using alternate nomenclature, this variant would be defined as BRCA1 5335A>T. This variant has been observed in at least two ovarian cancer patients with a family history of breast and/or ovarian cancer (Laplace-Marieze 1999, Ricevuto 2001). In functional studies this variant displayed impaired structural stability, binding activity, binding specificity, protein folding, transcription activity, cisplatin response, and ability to support growth (Lee 2010, Bouwman 2013). BRCA1 Asp1739Val was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Asp1739Val occurs at a position that is conserved in mammals and is located in the region of interaction with BRCA2 and multiple other proteins (Chen 1998, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider BRCA1 Asp1739Val to be a likely pathogenic variant. -

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:2Other:1

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 08, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Jun 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1739 of the BRCA1 protein (p.Asp1739Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with stomach and ovarian cancer (PMID: 10200350). ClinVar contains an entry for this variant (Variation ID: 55466). 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 expected to disrupt BRCA1 protein function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 23867111, 28781887, 30209399, 30765603). This variant disrupts the p.Asp1739 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12827452, 15800311, 19491284, 20516115, 23867111). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

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

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.93

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

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.0

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

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-7.4

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

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.0010, 1.0

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

Vest4

0.98

MVP

0.83

MPC

0.17

ClinPred

0.98

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.87

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

Other links and lift over