17-43049164-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_007294.4(BRCA1):​c.5363G>C​(p.Gly1788Ala) 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. G1788S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

BRCA1
NM_007294.4 missense

Scores

10
7
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3O:1

Conservation

PhyloP100: 4.31
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a domain BRCT 2 (size 99) in uniprot entity BRCA1_HUMAN there are 69 pathogenic changes around while only 15 benign (82%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43049165-C-T is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.935
PP5
Variant 17-43049164-C-G is Pathogenic according to our data. Variant chr17-43049164-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 531438.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA1NM_007294.4 linkc.5363G>C p.Gly1788Ala missense_variant Exon 21 of 23 ENST00000357654.9 NP_009225.1 P38398-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkc.5363G>C p.Gly1788Ala missense_variant Exon 21 of 23 1 NM_007294.4 ENSP00000350283.3 P38398-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2Other:1
Oct 11, 2020
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Brotman Baty Institute, University of Washington
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro

- -

May 05, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

A likely pathogenic variant was detected in this sample. This sequence change replaces glycine with alanine at codon 1809 of the BRCA1 protein (p.Gly1809Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (gnomAD). ClinVar contains an entry for this variant (Variation ID: 531438). This variant has been reported to affect BRCA1 protein function (PMID: 11016938, 30209399). This variant disrupts the p.Gly1809 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26689913, 17924331, 18418466, 9796975, 21990134, 27272900, 20516115). 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. This variant was confirmed by Sanger Sequencing . -

Hereditary breast ovarian cancer syndrome Pathogenic:1
Nov 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1788 of the BRCA1 protein (p.Gly1788Ala). This variant is not present in population databases (gnomAD no frequency). 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: 531438). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 11016938, 30209399). This variant disrupts the p.Gly1788 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9796975, 17924331, 18418466, 20516115, 21990134, 26689913, 27272900). 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
0.65
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.53
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.40
.;T;.;T;T;T;.;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.97
D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.3
.;M;.;.;.;.;.;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-4.7
D;N;.;.;.;.;N;D
REVEL
Pathogenic
0.87
Sift
Uncertain
0.0040
D;D;.;.;.;.;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D
Polyphen
0.34, 1.0
.;B;.;.;.;D;.;.
Vest4
0.90
MVP
0.99
MPC
0.26
ClinPred
0.98
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.81
gMVP
0.84

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.

Other links and lift over

dbSNP: rs80357069; hg19: chr17-41201181; API