chr17-43115750-G-C

Position:

chr17-43115750-G-C

Variant summary

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

The NM_007294.4(BRCA1):c.110C>G(p.Thr37Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,576 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T37K) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:2O:1

Conservation

PhyloP100: 4.40

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 links:

BRCA1 (HGNC:):

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a zinc_finger_region RING-type (size 41) in uniprot entity BRCA1_HUMAN there are 65 pathogenic changes around while only 6 benign (92%) 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 chr17-43115750-G-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.874

PP5

Variant 17-43115750-G-C is Pathogenic according to our data. Variant chr17-43115750-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 54132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.110C>G	p.Thr37Arg	missense_variant	3/23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.110C>G	p.Thr37Arg	missense_variant	3/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461414

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

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

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jun 08, 2010	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 01, 2021	The p.T37R pathogenic mutation (also known as c.110C>G), located in coding exon 2 of the BRCA1 gene, results from a C to G substitution at nucleotide position 110. The threonine at codon 37 is replaced by arginine, an amino acid with similar properties. This alteration has been identified in one woman belonging to an early onset breast cancer cohort (Haffty BG et al. J. Med. Genet. 2006 Feb; 43(2):133-7). Several independent DNA repair assays showed loss of function in p.T37R mutants for BRCA1 ubiquitin ligase activity, heterochromatin-mediated silencing, homology directed recombination, and single strand annealing (Morris JR et al. Hum Mol Genet. 2006; 15:599-606; Ransburgh DJ et al. Cancer Res. 2010; 70:988-95; Towler WI et al. Hum Mutat. 2013; Ruffner H et al. Proc. Natl. Acad. Sci. U.S.A. 2001 Apr; 98(9):5134-9; Zhu Q et al. Nature 2011 Sep; 477(7363):179-84). Another 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). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Brzovic PS et al. Nat. Struct. Biol. 2001 Oct;8(10):833-7; Ambry Internal Data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 15, 2021	- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 08, 2023

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 37 of the BRCA1 protein (p.Thr37Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 15983021, 19491284). ClinVar contains an entry for this variant (Variation ID: 54132). 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: 11320250, 19543972, 20103620, 30209399). This variant disrupts the p.Thr37 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19543972, 21990134, 25823446, 27272900, 28664506, 30209399). 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

0.96

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

.;T;.;.;.;D;.;T;T;.;T;D;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.87

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

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

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.4

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

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.017

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

Polyphen

1.0, 1.0

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

Vest4

0.94

MVP

0.97

MPC

0.47

ClinPred

0.99

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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