17-43092125-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_007294.4(BRCA1):​c.3406C>A​(p.Pro1136Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

1
6
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1O:1

Conservation

PhyloP100: 0.138
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29667145).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA1NM_007294.4 linkc.3406C>A p.Pro1136Thr missense_variant Exon 10 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.3406C>A p.Pro1136Thr missense_variant Exon 10 of 23 1 NM_007294.4 ENSP00000350283.3 P38398-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250892
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135704
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000199
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461320
Hom.:
0
Cov.:
39
AF XY:
0.00000138
AC XY:
1
AN XY:
726994
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.000111
Hom.:
0
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Sep 25, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P1136T variant (also known as c.3406C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 3406. The proline at codon 1136 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Mar 23, 2023
University of Washington Department of Laboratory Medicine, University of Washington
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Aug 31, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is located in the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a suspected hereditary breast and/or ovarian cancer family (PMID: 25136594). This variant has been identified in 2/250892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2
Jun 15, 2023
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 01, 2012
Sharing Clinical Reports Project (SCRP)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1Other:1
Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1136 of the BRCA1 protein (p.Pro1136Thr). This variant is present in population databases (rs431825395, gnomAD 0.02%). This missense change has been observed in individual(s) with familial breast and ovarian cancer (PMID: 25136594, 36881271). ClinVar contains an entry for this variant (Variation ID: 96911). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 80%. 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. -

-
GenomeConnect - Invitae Patient Insights Network
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 07-29-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
8.9
DANN
Benign
0.96
DEOGEN2
Uncertain
0.52
D;.;.;.
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.75
FATHMM_MKL
Benign
0.090
N
LIST_S2
Benign
0.83
T;T;T;T
M_CAP
Uncertain
0.22
D
MetaRNN
Benign
0.30
T;T;T;T
MetaSVM
Benign
-0.60
T
MutationAssessor
Uncertain
2.1
M;M;.;.
PrimateAI
Benign
0.29
T
PROVEAN
Pathogenic
-6.7
D;D;D;D
REVEL
Uncertain
0.49
Sift
Benign
0.11
T;T;T;T
Sift4G
Benign
0.29
T;T;T;T
Polyphen
0.48
P;.;.;P
Vest4
0.41
MutPred
0.35
Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);.;Gain of relative solvent accessibility (P = 0.0166);
MVP
0.55
MPC
0.37
ClinPred
0.13
T
GERP RS
-1.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.082
gMVP
0.17

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: rs431825395; hg19: chr17-41244142; API