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rs41293459

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_007294.4(BRCA1):c.5096G>T(p.Arg1699Leu) 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. R1699Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA1
NM_007294.4 missense

Scores

11
5
1

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2U:1O:1

Conservation

PhyloP100: 4.86
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 16 ACMG points.

PM1
In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 16 uncertain 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 chr17-43063930-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37636.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.867
PP5
Variant 17-43063930-C-A is Pathogenic according to our data. Variant chr17-43063930-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.5096G>T p.Arg1699Leu missense_variant 17/23 ENST00000357654.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.5096G>T p.Arg1699Leu missense_variant 17/231 NM_007294.4 P4P38398-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000157
Hom.:
0

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Uncertain:1Other:1
Uncertain significance, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)Dec 30, 1999- -
Likely pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Jun 28, 2023This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 30209399, 35196514]. -
not provided, no classification providedin vitroBrotman Baty Institute, University of Washington-- -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInvitaeNov 29, 2022This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 10923033). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1699 of the BRCA1 protein (p.Arg1699Leu). ClinVar contains an entry for this variant (Variation ID: 55398). 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 disrupts the p.Arg1699 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11157798, 17308087, 17574969, 20516115, 21324516, 21356067, 21473589, 22889855, 23867111, 25472942). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 25748678). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
Cadd
Pathogenic
29
Dann
Uncertain
1.0
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.79
D
MetaRNN
Pathogenic
0.87
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.94
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-5.3
D;N;.;D;.;.;N;D;D;D;D
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0020
D;D;.;D;.;.;D;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D;D;.;.;D
Polyphen
0.49, 1.0
.;P;.;.;.;D;.;.;.;D;.
Vest4
0.98
MVP
0.97
MPC
0.46
ClinPred
1.0
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.96
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.19
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: rs41293459; hg19: chr17-41215947; COSMIC: COSV100523072; COSMIC: COSV100523072; API