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rs80356860

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2_SupportingPM5PP3_ModeratePP5_Moderate

The NM_007294(BRCA1):c.5117G>T(p.Gly1706Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging 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. G1706A) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA1
NM_007294 missense

Scores

13
3
1

Clinical Significance

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

Conservation

PhyloP100: 4.86

Links

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
?
In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_007294
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 32.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr17-43063909-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37638. Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.887
PP5
?
Variant 17:43063909-C>A is Pathogenic according to our data. Variant chr17-43063909-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 868673. Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.5117G>T p.Gly1706Val missense_variant 17/23 ENST00000357654.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.5117G>T p.Gly1706Val missense_variant 17/231 NM_007294.4 P2P38398-1

Frequencies

GnomAD3 genomes
Cov.:
32

ClinVar

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

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInvitaeOct 13, 2022This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1706 of the BRCA1 protein (p.Gly1706Val). 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: 868673). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). This variant disrupts the p.Gly1706 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10755399, 11979449, 12385650, 15689452, 15923272, 17262179, 17308087, 17924331, 20516115, 20727672, 22144684, 23867111, 25948282, 27272900, 27616075, 28781887, 29446198, 30209399, 30458859). 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. -
Breast-ovarian cancer, familial, susceptibility to, 1 Other:1
not provided, no assertion providedin vitroBrotman Baty Institute, University of Washington-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
Cadd
Pathogenic
27
Dann
Uncertain
1.0
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
0.89
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.80
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.79
T
PROVEAN
Pathogenic
-6.8
D;N;.;D;.;.;N;D;D;D;D
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0010
D;D;.;D;.;.;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;.;.;D
Polyphen
0.72, 1.0
.;P;.;.;.;D;.;.;.;D;.
Vest4
0.95
MVP
0.98
MPC
0.50
ClinPred
0.99
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.93
gMVP
0.93

Splicing

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: rs80356860; hg19: chr17-41215926;