chr17-43063903-G-T

Position:

• chr17-43063903-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5123C>A​(p.Ala1708Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,684 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. A1708P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:35 O:1
• Conservation: PhyloP100: 6.18

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 12 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 16 uncertain in NM_007294.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• PP5: Variant 17-43063903-G-T is Pathogenic according to our data. Variant chr17-43063903-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 55407.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063903-G-T is described in Lovd as [Pathogenic]. Variant chr17-43063903-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5123C>A	p.Ala1708Glu	missense_variant	17/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5123C>A	p.Ala1708Glu	missense_variant	17/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251312 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461684 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000403 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:35 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:15 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Medical University Innsbruck	Feb 11, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Apr 09, 2020	This variant has been reported in the literature in multiple individuals and families with breast and/or ovarian cancer, and has been shown to segregate with disease (Lovelock 2006, Torres 2007, Millevoi 2010, Sagi 2011). This variant has an overall allele frequency of 0.00002 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, this variant is interpreted as pathogenic. PS4-moderate; PP1; PP3 -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 04, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PS3; PP3; PP1; Expert panel -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jan 29, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 05, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant replaces alanine with glutamic acid at codon 1708 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). RNA studies have reported varying degrees of exon 17 (BIC exon 18) skipping (PMID: 19404736, 20215541, 26780556). Functional studies have reported this variant impacts BRCA1 function in mammalian transcription activation assays (PMID: 15923272, 11157798, 17305420), complementation of BRCA1-deficient embryonic stem cells (PMID: 19770520, 23867111), a haploid cell proliferation assay (PMID: 30209399) and homology-directed repair and chromosome aberration assays (PMID: 34855882). This variant has been observed as a recurrent mutation in Spanish hereditary breast and ovarian cancer families (PMID: 10737987, 12955716, 23479189, 28477318) and in individuals and families affected with breast and ovarian cancer in other populations (PMID: 7939630, 9523200, 11157798, 15340362, 17080309, 19404736, 30606148, 30287823, 33471991, 34196900). This variant has been shown to segregate with disease in three pedigrees (PMID: 15923272). This variant has been identified in 5/251312 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	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 = 1 -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5242 C>A; This variant is associated with the following publications: (PMID: 21702907, 21447777, 21520273, 22044689, 21922593, 17305420, 24742220, 17924331, 12400015, 27286788, 28758972, 28680148, 28477318, 30606148, 28781887, 23867111, 20516115, 20378548, 20215541, 23233716, 11802208, 11157798, 17925560, 19404736, 9159158, 8942979, 8751436, 23199084, 23479189, 15923272, 18036263, 8872468, 18680205, 19770520, 25782689, 15235020, 7939630, 21990134, 25748678, 26071757, 26656232, 25085752, 27742776, 26780556, 27802165, 27272900, 27836010, 27533489, 28339459, 28283652, 28127413, 17080309, 28398198, 28918466, 27463008, 28528518, 28985766, 29021639, 29560538, 21063910, 29884136, 29088781, 29086229, 29433453, 30541753, 29321669, 29907814, 30209399, 30103829, 30630528, 30262796, 29446198, 30322717, 30765603, 27356891, 25525159, 32733560, 33067490, 31589614, 32341426, 32885271, 33087888, 30787465, 33087929) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 05, 2020	The BRCA1 c.5123C>A; p.Ala1708Glu variant (rs28897696), also known as 5242C>A, is a common recurrent variant in the Spanish population (de la Hoya 2002, Futreal 1994, Sanz 2010), and functional assays have confirmed this variant causes loss of function (Findlay 2018, Sanz 2010). This variant is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 55407). It is found in the general population with a low overall allele frequency of 0.002% (5/251312 alleles) in the Genome Aggregation Database. The alanine at codon 1708 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: de la Hoya M et al. Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing. Int J Cancer. 2002 Feb 1;97(4):466-71. Findlay GM et al. Accurate classification of BRCA1 variants with saturation genome editing. Nature. 2018 Oct;562(7726):217-222. Futreal PA et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994 Oct 7;266(5182):120-2. Sanz DJ et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res. 2010 Mar 15;16(6):1957-67. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 09, 2019	The BRCA1 c.5123C>A (p.Ala1708Glu) variant has been reported in the published literature in individuals and families affected with breast or ovarian cancer (PMID: 28477318 (2017), 23233716 (2013), 22399190 (2012), 17924331 (2007), 12955716 (2003), 11802208 (2002)). Additionally, functional studies indicate that this variant has a damaging effect on BRCA1 protein structure and function and may result in aberrant BRCA1 mRNA splicing (PMID: 19404736 (2010), 20516115 (2010), 18036263 (2007), 12400015 (2002), 11157798 (2001)). The frequency of this variant in the general population, 0.000058 (2/34580 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Considered pathogenic based on Myriad report from BB4536. NVA Still recommended. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 22, 2021	- -

Hereditary breast ovarian cancer syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1708 of the BRCA1 protein (p.Ala1708Glu). This variant is present in population databases (rs28897696, gnomAD 0.006%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 15923272, 17080309, 19404736, 21063910). It has also been observed to segregate with disease in related individuals. This variant is also known as 5242C>A. ClinVar contains an entry for this variant (Variation ID: 55407). 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: 11157798, 15923272, 17305420, 19770520, 20516115, 25748678). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 26, 2017	Variant summary: The BRCA1 c.5123C>A (p.Ala1708Glu) variant involves the alteration of a conserved nucleotide located in the BRCT domain of the protein (InterPro). 5/5 in silico tools predict a damaging outcome for this substitution. This variant was found in 3/120626 control chromosomes at a frequency of 0.0000249, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). It was reported in several HBOC patients indicating pathogenicity. Additionally, a functional study demonstrated the variant to result in inappropriate skipping of the entire exon 18, to reduce structural stability, phosphopeptide binding and transcription activity further supporting a deleterious impact. Several variants affecting the same codon are reported in UMD/HGMD/ClinVar such as UMD: c.5123C>G (p.Ala1708Gly), c.5123C>T (p.Ala1708Val), c.5123delC (p.Ala1708GlyfsX6), c.5124G>A (p.Ala1708Ala), c.5122G>C (p.Ala1708Pro) indicating the variant to be located in a mutational hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2019	The p.Ala1708Glu variant in BRCA1 has been reported in more than 40 individuals with hereditary breast and ovarian cancer (HBOC) and segregated with disease in at least 5 affected relatives from 3 families (Futreal 1994, Greenman 1998, Blesa 2000, de la Hoya 2002, Infante 2006, Torres 2007, Laitman 2011, Sagi 2011, Laitman 2012, Rodriguez 2012, de Juan 2013, Hernandez 2014). It has also been identified in 2/34580 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of HBOC in the general population. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In vitro functional studies provide some evidence that the p.Ala1729Glu variant may cause skipping of exon 18 (Millevoi 2010, Sanz 2010). In addition, this variant was classified as Pathogenic on Aug 10, 2015 by the ClinGen-approved ENIGMA Expert Panel (ClinVar SCV000244385.1). In summary, the p.Ala1729Glu variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2, PS3_Moderate, PP1_Moderate. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 22, 2021	The p.A1708E pathogenic mutation (also known as c.5123C>A), located in coding exon 16 of the BRCA1 gene, results from a C to A substitution at nucleotide position 5123. The alanine at codon 1708 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration has been reported in numerous high-risk breast/ovarian cancer families (Fernandez-Lopez JC et al. Hum Genomics 2019 01;13(1):3; Abdel-Razeq H et al. J Oncol 2020 Jul;2020:8362179; Vallon-Christersson J et al. Hum. Mol. Genet. 2001 Feb;10:353-60; Abkevich V et al. J. Med. Genet. 2004 Jul;41:492-507; Capanu M et al. Genet. Epidemiol. 2011 Jul;35:389-97; Gabaldó Barrios X et al. Fam. Cancer. 2017 Oct;16:477-489) and has been described as a founder mutation in the Colombian, Spanish, and Sephardic Jewish populations (Ferla R et al. Ann. Oncol. 2007 Jun;18 Suppl 6:vi93-8; Janavicius R. EPMA J. 2010 Sep;1:397-412; Sagi M et al. Fam. Cancer. 2011 Mar;10:59-63). Multiple functional studies have classified this alteration as deleterious (Findlay GM et al. Nature 2018 10;562(7726):217-222; Thouvenot P et al. PLoS Genet. 2016 06;12:e1006096; Bouwman P et al. Cancer Discov. 2013 Oct;3:1142-55; Lovelock PK et al. J. Med. Genet. 2006 Jan;43:74-83). A statistical algorithm based on personal and family history of cancer has also classified this alteration as pathogenic (Pruss D et al. Breast Cancer Res. Treat. 2014 Aug;147:119-32). In addition, p.A1708E was 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, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). Of note, this alteration is also referred to as 5242C>A in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 02, 2023	This missense variant replaces alanine with glutamic acid at codon 1708 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). RNA studies have reported varying degrees of exon 17 (BIC exon 18) skipping (PMID: 19404736, 20215541, 26780556). Functional studies have reported this variant impacts BRCA1 function in mammalian transcription activation assays (PMID: 15923272, 11157798, 17305420), complementation of BRCA1-deficient embryonic stem cells (PMID: 19770520, 23867111), a haploid cell proliferation assay (PMID: 30209399) and homology-directed repair and chromosome aberration assays (PMID: 34855882). This variant has been observed as a recurrent mutation in Spanish hereditary breast and ovarian cancer families (PMID: 10737987, 12955716, 23479189, 28477318) and in individuals and families affected with breast and ovarian cancer in other populations (PMID: 7939630, 9523200, 11157798, 15340362, 17080309, 19404736, 30606148, 30287823, 33471991, 34196900). This variant has been shown to segregate with disease in three pedigrees (PMID: 15923272). This variant has been identified in 5/251312 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 18, 2022	- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 02, 2022

- -

Breast neoplasm Pathogenic:1

Pathogenic, criteria provided, single submitter

research

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

-

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 21, 2021

Invasive ductal carcinoma EST= - PRO = - HER2 = - KI = 75% -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	.;T;.;.;T;T;.;.;.;T;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.1	.;M;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.7	D;N;.;D;.;.;N;D;D;N;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;.;D;.;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;.;.;D
Polyphen		0.99, 1.0	.;D;.;.;.;D;.;.;.;D;.
Vest4		0.92
MVP		0.97
MPC		0.47
ClinPred		0.84	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs28897696; hg19: chr17-41215920; COSMIC: COSV58803602; COSMIC: COSV58803602;