17-43106457-T-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_007294.4(BRCA1):​c.211A>T​(p.Arg71Trp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. R71G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA1
NM_007294.4 missense, splice_region

Scores

9
8
2
Splicing: ADA: 0.9999
2

Clinical Significance

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

Conservation

PhyloP100: 4.16
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 12 ACMG points.

PM1
In a mutagenesis_site No effect on interaction with BAP1. (size 0) in uniprot entity BRCA1_HUMAN there are 6 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 chr17-43106457-T-C is described in Lovd as [Pathogenic].
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 17-43106457-T-A is Pathogenic according to our data. Variant chr17-43106457-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 867340.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.211A>T p.Arg71Trp missense_variant, splice_region_variant 4/23 ENST00000357654.9 NP_009225.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.211A>T p.Arg71Trp missense_variant, splice_region_variant 4/231 NM_007294.4 ENSP00000350283 P4P38398-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 27, 2019The c.211A>T variant (also known as p.R71W), located in coding exon 3 of the BRCA1 gene, results from an A to T substitution at nucleotide position 211. The arginine at codon 71 is replaced by tryptophan, an amino acid with dissimilar properties. One functional study found that c.211A>T is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). A similar alteration affecting this same nucleotide, c.211A>G, has been reported in numerous breast and ovarian cancer patients and families (Villarreal-Garza C et al. Breast Cancer Res. Treat. 2015 Apr;150:389-94; Janavièius R. EPMA J. 2010 Sep;1:397-412; Diez O et al. Int. J. Cancer. 1999 Nov;83:465-9; Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18(1):112; Alvarez C et al. Oncotarget, 2017 Sep;8:74233-74243; Yang XR et al. Breast Cancer Res. Treat. 2017 Oct;165(3):687-697; Cotrim DP et al. BMC Cancer, 2019 Jan;19:4) and was observed to result in aberrant splicing, including exon 5 skipping, due to the use of a cryptic splice donor site (Sanz DJ et al. Clin. Cancer Res. 2010 Mar;16:1957-67; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38). Using the BDGP and ESEfinder splice site prediction tools, c.211A>T is predicted to have the same impact on splicing as c.211A>G and is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1 Other:1
not provided, no classification providedin vitroBrotman Baty Institute, University of Washington-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Benign
0.32
.;T;.;.;.;.;T;.;.;T;T;T;T;.
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.80
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.84
D
MutationAssessor
Uncertain
2.5
M;M;M;M;.;M;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;N;N;N;N;N
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-2.9
D;N;N;D;N;D;D;N;N;.;N;N;D;.
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;.;D;D;D;.
Sift4G
Uncertain
0.0020
D;D;D;D;D;D;.;D;D;.;D;D;.;.
Polyphen
1.0, 1.0
.;D;.;.;.;D;.;.;D;.;.;.;.;.
Vest4
0.80
MutPred
0.62
Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);.;Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);.;Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);Loss of disorder (P = 0.0025);.;
MVP
0.97
MPC
0.41
ClinPred
0.97
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.68
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.63
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.63
Position offset: -1

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: rs80357382; hg19: chr17-41258474; API