17-43063941-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PM5BP4BP6

The NM_007294.4(BRCA1):​c.5085T>A​(p.Phe1695Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. F1695?) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA1
NM_007294.4 missense

Scores

3
4
12

Clinical Significance

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

Conservation

PhyloP100: 1.51
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a strand (size 2) in uniprot entity BRCA1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chr17-43063941-AAA-AC is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.39142215).
BP6
Variant 17-43063941-A-T is Benign according to our data. Variant chr17-43063941-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55389.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkc.5085T>A p.Phe1695Leu missense_variant 17/23 ENST00000357654.9 NP_009225.1 P38398-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkc.5085T>A p.Phe1695Leu missense_variant 17/231 NM_007294.4 ENSP00000350283.3 P38398-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251232
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135814
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:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Other:1
not provided, no classification providedin vitroBrotman Baty Institute, University of Washington-- -
Uncertain significance, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)Jun 22, 1999- -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 26, 2023Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 16528612, 20516115, 30209399, 30257991). 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. 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. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1695 of the BRCA1 protein (p.Phe1695Leu). This variant is present in population databases (rs80357387, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 12827452). ClinVar contains an entry for this variant (Variation ID: 55389). -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 10, 2020This 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
0.60
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Benign
17
DANN
Benign
0.92
DEOGEN2
Benign
0.13
.;T;.;.;T;T;.;.;.;T;.
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.16
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.86
D;D;D;T;D;T;D;D;D;D;D
M_CAP
Pathogenic
0.77
D
MetaRNN
Benign
0.39
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.44
D
MutationAssessor
Benign
0.14
.;N;.;.;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-0.69
N;N;.;N;.;.;N;N;N;N;N
REVEL
Uncertain
0.48
Sift
Benign
0.50
T;T;.;T;.;.;T;T;T;T;T
Sift4G
Benign
1.0
T;T;T;T;T;T;T;T;.;.;T
Polyphen
0.24, 0.0060, 0.12
.;B;.;.;.;B;.;.;.;B;.
Vest4
0.42
MVP
0.83
MPC
0.26
ClinPred
0.32
T
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.28
gMVP
0.47

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.

Other links and lift over

dbSNP: rs80357387; hg19: chr17-41215958; API