NM_007294.4:c.115T>C

Variant names:

• chr17-43115745-A-G
• rs80357164
• NM_007294.4:c.115T>C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.115T>C​(p.Cys39Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,446 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C39F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:16 U:1 O:1
• Conservation: PhyloP100: 4.11

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 chr17-43115744-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 17-43115745-A-G is Pathogenic according to our data. Variant chr17-43115745-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 54152.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115745-A-G is described in Lovd as [Pathogenic]. Variant chr17-43115745-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.115T>C	p.Cys39Arg	missense_variant	Exon 3 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.115T>C	p.Cys39Arg	missense_variant	Exon 3 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461446 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727002

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:9 Uncertain:1 Other:1

Jan 02, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.115T>C variant is classified as Pathogenic (PS1, PS3, PM2, PP5) The BRCA1 c.115T>C variant is a single nucleotide change in the BRCA1 gene, which is predicted to change the amino acid cysteine at position 39 in the protein to arginine. This variant is absent from population databases (PM2). Well-established functional studies show a deleterious effect of this variant (PS3). Assay of Cys39 to Tyr and Arg indicate affect on double strand break repair and centrosome duplication. This variant results in the same amino acid change as a previously established variant (PS1). All changes from cysteine regarded as pathogenic - cysteine involved in disulphide bridge The variant has been reported in dbSNP (rs80357164) and in the HGMD database: CM040687. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 54152). -

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Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Jul 15, 2008

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2017

Genologica Medica

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2021

Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

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

- -

Feb 01, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115T>C (p.Cys39Arg) variant in the BRCA1 gene has been reported in multiple patients with hereditary breast and ovarian cancer (PMID 12827452, 18489799, 28993434). This variant is absent from large databases of genetic variation in the general population. Functional classification using saturation genome editing showed that this variant to be loss-of-function (PMID 30209399). Multiple lines of prediction algorithms support the deleterious effect of the variant. Loss of function variants in the BRCA1 gene have been associated with familial breast-ovarian cancer-1 (BROVCA1, MIM# 604370). Therefore, c.115T>C (p.Cys39Arg) variant in the BRCA1 gene is classified as pathogenic. -

Dec 28, 2015

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces a conserved cysteine with arginine at codon 39 in the RING domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373).Functional studies have reported that this variant impacts BRCA1 function in ubiquitin ligase, homology-directed repair, haploid cell proliferation assays and binding assays to known protein-protein interacting partners (PMID: 16403807, 25823446, 30209399, 30219179, 37168384). This variant has been reported in over 10 individuals and families affected with breast and/or ovarian cancer (PMID: 12827452, 15024741, 17319787, 18489799, 19543972, 26757417, 30287823). Several different missense substitutions at p.Cys39 has been reported as disease-causing in ClinVar (variation ID: 37392, 37393, 54151, 54153, 267497). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Aug 10, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.99 -

not provided Pathogenic:2

Oct 03, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: impairs E2 and BARD1 binding and reduces E3 ubiquitin ligase activity (Morris et al., 2006; Starita et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with Hereditary Breast and Ovarian Cancer syndrome (Rostagno et al., 2003; Machackova et al., 2008; Sweet et al., 2010; Konecny et al., 2011; Lhota et al., 2016; Ng et al., 2016; Wen et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 234T>C; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 15235020, 22753008, 26822949, 26757417, 18493658, 30040829, 29884136, 21990134, 15024741, 18489799, 24489791, 21203900, 12827452, 27272900, 16403807, 25823446, 19543972, 30209399, 29446198, 28993434, 33087888, 24389207, 20104584, 8944023) -

Dec 05, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Statistically enriched in patients compared to ethnically matched controls. Not found in the total gnomAD dataset, and the data is high quality (0/282180 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 11, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C39R pathogenic mutation (also known as c.115T>C), located in coding exon 2 of the BRCA1 gene, results from a T to C substitution at nucleotide position 115. The cysteine at codon 39 is replaced by arginine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple hereditary breast and/or ovarian cancer families (Rostagno P et al. J. Hum. Genet., 2003 Jul;48:362-6; Machackova E et al. BMC Cancer, 2008 May;8:140; Konecny M et al. Breast Cancer Res. Treat., 2011 Feb;126:119-30). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). One other functional study has demonstrated that p.C39R causes abolishment and decreased activity of ubiquitin protein ligase function in the BRCA1 RING finger in vitro (Morris JR et al. Hum. Mol. Genet., 2006 Feb;15:599-606). Additional functional studies using yeast assays have shown that this mutation results in deficient protein compared to wild-type BRCA1 (Thouvenot P et al. PLoS Genet., 2016 06;12:e1006096). The p.C39R alteration is located in a critical region of the BRCA1 protein RING domain, and, along with other alterations at this codon including p.C39Y and p.C39S, has been shown to alter the structure of the RING domain and negatively impact protein function and binding (Ruffner H et al. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5134-9; Brzovic PS et al. Proc Natl Acad Sci USA. 2003 May;100(10):5646-51; Ransburgh DJ et al. Cancer Res. 2010 Feb 1;70(3):988-95; Sweet K et al. Breast Cancer Res Treat. 2010 Feb;119(3):737-43). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Of note, this alteration has also been designated as 234T>C in published literature. Based on the supporting evidence to date, this alteration is interpreted as a disease-causing mutation. -

Apr 05, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Aug 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 39 of the BRCA1 protein (p.Cys39Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12827452, 15024741, 18489799, 21203900, 26822949). ClinVar contains an entry for this variant (Variation ID: 54152). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 12732733, 16403807, 22843421, 24489791, 25823446). This variant disrupts the p.Cys39 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9808526, 11320250, 17262179, 18500671, 19504351, 23683081, 25823446). 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. -

Breast and/or ovarian cancer Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;T;.;.;.;D;.;T;T;.;D;D;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.4	H;H;H;H;H;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.76	N;N;N;D;N;D;N;.;N;N;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.028	D;D;D;D;D;.;D;.;D;.;D;.;.
Polyphen		0.99, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.94
MutPred		1.0		Gain of catalytic residue at C39 (P = 0.0465);Gain of catalytic residue at C39 (P = 0.0465);Gain of catalytic residue at C39 (P = 0.0465);Gain of catalytic residue at C39 (P = 0.0465);Gain of catalytic residue at C39 (P = 0.0465);Gain of catalytic residue at C39 (P = 0.0465);Gain of catalytic residue at C39 (P = 0.0465);Gain of catalytic residue at C39 (P = 0.0465);Gain of catalytic residue at C39 (P = 0.0465);Gain of catalytic residue at C39 (P = 0.0465);Gain of catalytic residue at C39 (P = 0.0465);Gain of catalytic residue at C39 (P = 0.0465);Gain of catalytic residue at C39 (P = 0.0465);
MVP		1.0
MPC		0.53
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.94

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

Other links and lift over

dbSNP: rs80357164; hg19: chr17-41267762;