17-43115744-C-T

Variant names:

• chr17-43115744-C-T
• rs80357498
• NM_007294.4:c.116G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.116G>A​(p.Cys39Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. C39R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 U:1
• Conservation: PhyloP100: 3.48
• Publications: 59 publications found

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

ACMG classification

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

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 16 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 chr17-43115745-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 54152.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-43115744-C-T is Pathogenic according to our data. Variant chr17-43115744-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37392.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	c.116G>A	p.Cys39Tyr	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.116G>A	p.Cys39Tyr	missense_variant	Exon 3 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000251 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7 Uncertain:1

Dec 11, 2006

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

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

- -

Oct 02, 2023

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 cysteine with tyrosine at codon 39 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 homology-directed DNA repair, ubiquitin E3 ligase, haploid cell proliferation, centrosome duplication and yeast colony size assays (PMID: 11320250, 20103620, 21725363, 23161852, 25823446, 27272900, 30209399). This variant has been detected in at least eight individuals affected with breast and/or ovarian cancer and additional suspected hereditary breast and ovarian cancer families (PMID: 9808526, 22752604, 22923021, 26852130, 32894085). Other missense substitutions at this codon to serine, arginine, glycine, phenylalanine and tryptophan also have been reported as disease-causing in ClinVar (variation ID 37393, 54151, 54152, 54153, 267497, 867499). This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 09, 2022

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3, PS4_STR, PM2_SUP, PM5 -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

Jun 15, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4

Apr 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in multiple Hereditary Breast and Ovarian Cancer families, and has been described as a pathogenic founder variant from regions of Italy and Slovenia (Santarosa 1998, Stegel 2011, Juwle 2012, Novakovic 2012, Krajc 2014, Cini 2016); Published functional studies demonstrate a damaging effect: defective ubiquitin ligase activity, homology directed repair activity, BARD1 binding, double-strand break repair, and classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Ruffner 2001, Ransburgh 2010, Millot 2011, Kais 2012, Towler 2013, Findlay 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 235G>A; This variant is associated with the following publications: (PMID: 26852130, 21232165, 22923021, 15385441, 20103620, 30733539, 29446198, 21922593, 23161852, 15235020, 21725363, 11320250, 9808526, 22752604, 23397983, 25823446, 27272900, 30209399, 30696104, 30040829, 32719484, 30078507, 24389207, 20104584, 8944023, 33087888) -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.000032 (1/31396 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMIDs: 9808526 (1998), 22923021 (2012), 23397983 (2014), 26852130 (2016), 30078507 (2018), 29446198 (2018), and 32772980 (2020). Functional studies report a reduction of E3 ubiquitin ligase activity, RING domain binding, resistance to ionizing radiation, and DNA repair ability (PMIDs: 11320250 (2001), 20103620 (2010), 25823446 (2015), and 33087888 (2021)). Additionally, the variant is linked to the amplification of centromeres, leading to an increase in abnormal chromosomes within cells (PMID: 21725363 (2012)). Yeast assays further support the variant's pathogenicity via colony growth patterns (PMID: 21922593 (2011). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Dec 20, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C39Y pathogenic mutation (also known as c.116G>A), located in coding exon 2 of the BRCA1 gene, results from a G to A substitution at nucleotide position 116. The cysteine at codon 39 is replaced by tyrosine, an amino acid with highly dissimilar properties. The cysteine at codon 39 is a putative zinc-binding residue occurring in the functionally important RING domain of the BRCA1 protein. Cells with p.C39Y are deficient in the control of centrosome number (Kais Z et al. Oncogene. 2012 Feb 9;31(6):799-804). Other studies have demonstrated abolishment and decreased activity of ubiquitin protein ligase function the BRCA1 RING finger in vitro (Ruffner H et al. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5134-9; Starita LM et al. Genetics. 2015 Jun;200(2):413-22). In addition, p.C39Y failed to reverse gamma radiation (IR) hypersensitivity in vivo (Ruffner H et al. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5134-9). Furthermore, cells with p.C39Y were found to be defective in the repair of double-strand breaks by homology-directed recombination (HDR) and double-strand break repair by the single-strand annealing (SSA) pathway (Towler WI et al. Hum Mutat. 2013 Mar;34(3):439-45). Other studies found cells with p.C39Y to be deficient in BARD1 binding (Ransburgh DJ et al. Cancer Res. 2010 Feb 1;70(3):988-95; Starita LM et al. Genetics. 2015 Jun;200(2):413-22). 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). In addition to these functional studies, this mutation has been identified in multiple breast and/or ovarian cancer families to date (Santarosa M et al. Int J Cancer. 1998 Nov 23;78(5):581-6; Stegel V et al. BMC Med Genet. 2011 Jan 14;12:9; Juwle A et al. Med Oncol. 2012 Dec;29(5):3272-81; Krajc M et al. Clin Genet, 2014 Jan;85:59-63; Cini G et al. BMC Med Genet, 2016 Feb;17:11; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Bakkach J et al. BMC Cancer, 2020 Sep;20:859). Furthermore, a different alteration at the same codon, p.C39R, has been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8). 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. -

Apr 05, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jul 31, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with tyrosine at codon 39 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 homology-directed DNA repair, ubiquitin E3 ligase, haploid cell proliferation, centrosome duplication and yeast colony size assays (PMID: 11320250, 20103620, 21725363, 23161852, 25823446, 27272900, 30209399). This variant has been detected in at least eight individuals affected with breast and/or ovarian cancer and additional suspected hereditary breast and ovarian cancer families (PMID: 9808526, 22752604, 22923021, 26852130, 32894085). Other missense substitutions at this codon to serine, arginine, glycine, phenylalanine and tryptophan also have been reported as disease-causing in ClinVar (variation ID 37393, 54151, 54152, 54153, 267497, 867499). This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Apr 18, 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 tyrosine, which is neutral and polar, at codon 39 of the BRCA1 protein (p.Cys39Tyr). This variant is present in population databases (rs80357498, gnomAD 0.007%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9808526, 21232165, 22752604, 22923021, 23397983, 26852130). This variant is also known as 235G>A. ClinVar contains an entry for this variant (Variation ID: 37392). 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: 11320250, 20103620, 21725363, 21922593, 23161852, 27272900). 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: 12827452, 18500671, 19504351, 19543972, 21990134, 23683081). 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. -

Dec 17, 2015

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Breast neoplasm Pathogenic:1

Aug 19, 2017

3DMed Clinical Laboratory Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of urinary bladder Pathogenic:1

-

Laboratory of Urology, Hospital Clinic de Barcelona

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	.;T;.;.;.;D;.;T;T;.;T;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T;T;T;T;D;T;T;D;T;T;T;T;T
M_CAP	Pathogenic	0.83	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	4.0	H;H;H;H;H;.;.;.;.;.;.;.;.
PhyloP100		3.5
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.7	N;N;N;N;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	0.024	D;D;D;D;D;.;D;.;D;.;D;.;.
Polyphen		1.0, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.92
MutPred		1.0		Loss of methylation at K38 (P = 0.1129);Loss of methylation at K38 (P = 0.1129);Loss of methylation at K38 (P = 0.1129);Loss of methylation at K38 (P = 0.1129);Loss of methylation at K38 (P = 0.1129);Loss of methylation at K38 (P = 0.1129);Loss of methylation at K38 (P = 0.1129);Loss of methylation at K38 (P = 0.1129);Loss of methylation at K38 (P = 0.1129);Loss of methylation at K38 (P = 0.1129);Loss of methylation at K38 (P = 0.1129);Loss of methylation at K38 (P = 0.1129);Loss of methylation at K38 (P = 0.1129);
MVP		1.0
MPC		0.57
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80357498; hg19: chr17-41267761;