chr17-43106456-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_007294.4(BRCA1):c.212G>C(p.Arg71Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R71S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA1
NM_007294.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.11

Publications

56 publications found

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]

BRCA1 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Fanconi anemia, complementation group S
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
pancreatic cancer, susceptibility to, 4
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 20 benign, 82 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 chr17-43106457-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 17693.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-43106456-C-G is Pathogenic according to our data. Variant chr17-43106456-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 267512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.212G>C	p.Arg71Thr	missense_variant, splice_region_variant	Exon 4 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.212G>C	p.Arg71Thr	missense_variant, splice_region_variant	Exon 4 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:2

May 31, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Jun 10, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant alters the conserved guanine at the last nucleotide position of exon 4 of the BRCA1 gene. This variant is also known as 331G>C in exon 5 according to the BIC nomenclature and exon naming system. This variant is predicted to disrupt the reference intron 4 splice donor site and also to activate an out-of-frame cryptic donor site (PMID: 35449021). Two other mutations c.212G>A and c.211A>G have been shown to cause out-of-frame splicing (PMID: 11385711, 20215541, 21863257, 22505045, 23451180) and also the in-frame skipping of exon 4 impacting the functionally important RING domain (PMID: 21863257). These aberrant spliced transcript are expected to produce an absent or nonfunctional protein product. Functional studies have reported findings consistent with this variant causing unstable mRNA thus impacting BRCA1 function (PMID: 30209399), whereas the variant protein change (p.Arg71Thr) on its own had no impact on BARD1 binding and E3 ligase assays (PMID: 25823446, 35659930). This variant has been reported in an individual affected with ovarian cancer (PMID: 29053726). Similar variants c.211A>G and c.212G>A have been reported in individuals and families affected with breast or ovarian cancer (PMID: 11385711, 11802209, 21863257, 23683081, 25480878, 26577449, 27081505, 28724667, 29435039, 29752822, 30078507) and c.211A>G also has been reported to segregate with disease with a likelihood ratio for pathogenicity of 383.2656 (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

May 06, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.212G>C pathogenic mutation (also known as p.R71T), located in coding exon 3 of the BRCA1 gene, results from a G to C substitution at nucleotide position 212. The arginine at codon 71 is replaced by threonine, an amino acid with similar properties. This change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. This alteration was identified in an individual diagnosed with ovarian cancer (Harter P et al. PLoS ONE, 2017 Oct;12:e0186043) and in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data).One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Another alteration impacting the same donor site (p.R71G, c.211A>G) has been has been shown to have a similar impact on splicing (Ambry internal data; Sanz DJ et al. Clin. Cancer Res. 2010 Mar;16:1957-67; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38).This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Ovarian neoplasm

Pathogenic:1

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

May 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 71 of the BRCA1 protein (p.Arg71Thr). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. 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: 267512). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg71 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.32

.;T;.;.;.;.;T;.;.;T;T;T;T;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.65

MetaRNN

Uncertain

0.74

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.5

M;M;M;M;.;M;.;.;.;.;.;.;.;.

PhyloP100

4.1

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.4

N;N;N;N;N;N;D;N;N;.;N;N;D;.

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;.;D;D;D;.

Sift4G

Uncertain

0.012

D;D;D;D;D;D;.;D;D;.;D;D;.;.

Polyphen

0.30, 0.99, 1.0

.;B;.;.;.;D;.;.;D;.;.;.;.;.

Vest4

0.76

MutPred

0.59

Gain of ubiquitination at K70 (P = 0.0719);Gain of ubiquitination at K70 (P = 0.0719);Gain of ubiquitination at K70 (P = 0.0719);Gain of ubiquitination at K70 (P = 0.0719);.;Gain of ubiquitination at K70 (P = 0.0719);Gain of ubiquitination at K70 (P = 0.0719);.;Gain of ubiquitination at K70 (P = 0.0719);Gain of ubiquitination at K70 (P = 0.0719);Gain of ubiquitination at K70 (P = 0.0719);Gain of ubiquitination at K70 (P = 0.0719);Gain of ubiquitination at K70 (P = 0.0719);.;

MVP

0.96

MPC

0.25

ClinPred

0.92

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.78

gMVP

0.62

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.65

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.65

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over