17-43063937-A-G

Position:

• chr17-43063937-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP4_Strong PS3 PP1_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.5089T>C variant in BRCA1 is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 1697 (p.Cys1697Arg). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.40, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.05 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, 30257991, 30765603) (PS3 met). Cosegregation analysis of family(ies) carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 5.24, within the thresholds for moderate pathogenic evidence (LR >4.3 & ≤18.7) (PP1_Moderate met; internal lab contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2735.2 (based on Cosegregation LR=730.6; Pathology LR=2.41; Family History LR=1.56), above the thresholds for Very strong evidence towards pathogenicity (LR>350) (PP4_Very strong met; PMID:31131967, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3, PP1_Moderate, PP4_Very strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA003228/MONDO:0011450/092

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 U:2 O:1
• Conservation: PhyloP100: 5.76

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5089T>C	p.Cys1697Arg	missense_variant	17/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5089T>C	p.Cys1697Arg	missense_variant	17/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3 Uncertain:2 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Apr 12, 1999	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 24, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 19, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PP3; PS3; PP1_Moderate; PM2_Supporting; PP4_Very_strong -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2022	Observed in individuals with BRCA1-related cancers (Bergthorsson 2001, Vallon-Christersson 2001, Malander 2004, Cruger 2005, Thomassen 2008); Published functional studies demonstrate a damaging effect: impaired transcriptional activity, binding capacity, protein folding and stability, homologous recombination, cell survival, nuclear localization, and protein expression (Vallon-Christersson 2001, Glover 2006, Lee 2010, Anantha 2017, Findlay 2018, Petitalot 2019, Fernandes 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 5208T>C; This variant is associated with the following publications: (PMID: 15133502, 30209399, 21447777, 17305420, 11389159, 20516115, 30415210, 30765603, 28398198, 16528612, 14534301, 31131967, 30257991, 18465347, 14746861, 31409081, 24729269, 10946236, 28277317, 24845084, 11157798, 20423312, 24772314, 28781887, 16098011, 32341426, 33087888, 31742824, 25348405) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 01, 2019	Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

BRCA1-related cancer predisposition Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen

Jun 11, 2024

The c.5089T>C variant in BRCA1 is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 1697 (p.Cys1697Arg). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.40, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.05 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, 30257991, 30765603) (PS3 met). Cosegregation analysis of family(ies) carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 5.24, within the thresholds for moderate pathogenic evidence (LR >4.3 & <=18.7) (PP1_Moderate met; internal lab contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2735.2 (based on Cosegregation LR=730.6; Pathology LR=2.41; Family History LR=1.56), above the thresholds for Very strong evidence towards pathogenicity (LR>350) (PP4_Very strong met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3, PP1_Moderate, PP4_Very strong). -

Malignant tumor of breast Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Cys1697Arg variant was identified in 9 of 1204 proband chromosomes (frequency 0.007) from Danish and Swedish individuals or families with hereditary breast and/or ovarian cancer, bilateral or multifocal breast cancer, or invasive epithelial ovarian carcinoma, and was not identified in 360 control chromosomes from healthy individuals (Malander_2004_14746861, Thomassen_2008_18465347, Bergthorsson_2001_11389159). It was not identified in the GeneInsight-COGR, COSMIC, MutDB, ARUP Laboratories, or Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs80356993) as “With Likely pathogenic, Uncertain significance allele”, ClinVar and Clinvitae (1x classified as likely pathogenic by Ambry Genetics; 2x classified as uncertain significance by SCRP and BIC; 1x not classified by Invitae), LOVD 3.0 (10x with multiple functional study citations), UMD-LSDB (predicted to be pathogenic), BIC Database (3 samples recorded with clinical importance classified as unknown) databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). Multiple functional studies have investigated the effect of this variant. Limited proteolysis to determine stability of the protein fold using in vitro transcribed/translated material noted that the C1697R mutant showed a particularly low protein expression level (Lee_2010_20516115). Using yeast and mammalian-based transcription assays this variant displayed loss of transcriptional activity, suggesting that it represents a disease-associated mutation, in agreement with pedigree analysis (Vallon-Christersson_2001_11157798). This study notes that C1697R is a dramatic amino acid substitution, from a non-polar residue capable of forming disulfide linkages to a positively charged residue, located in a critical alpha-helix based on the structure of XRCC1 BRCT, and that this variant was found to segregate with disease in 1 family in the study and 3 other breast cancer patients from another study (Bergthorsson_2001_11389159). In a protease-based assay, substitution of arginine showed increased sensitivity to chymotryptic cleavage at 20°C, suggesting that destabilizing effects, rather than the introduction of a new trypsin cleavage site, are responsible for the protease sensitivity (Williams_2003_14534301). A peptide-binding assay determined that the variant has a severe folding effect (Williams_2004_15133503). In a study which screened DNA using SSCA and PTT, the BRCA1 construct containing Arg1697 was not able to activate transcription in this system, supporting the classification of C1697R as a pathogenic mutation (Bergthorsson_2001_11389159). The p.Cys1697Arg residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2023

The p.C1697R variant (also known as c.5089T>C), located in coding exon 16 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5089. The cysteine at codon 1697 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been identified in several breast/ovarian cancer kindreds and has not been reported in control populations (Bergthorsson JT, J. Med. Genet. 2001 Jun; 38(6):361-8; Malander S, Eur. J. Cancer 2004 Feb; 40(3):422-8; Thomassen M, Acta Oncol 2008; 47(4):772-7; Biunno I et al. Fam Cancer, 2014 Sep;13:437-44; Machackova E et al. Klin Onkol, 2019;32:51-71; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Dorling et al. N Engl J Med. 2021 02;384:428-439). Structural modeling and functional assays evaluating homology directed DNA repair, proteolytic degradation, protein stability, transcriptional activation, and peptide binding ability have suggested that this alteration results in reduced or loss of wild type function (Vallon-Christersson J, Hum. Mol. Genet. 2001 Feb; 10(4):353-60; Williams RS, J. Biol. Chem. 2003 Dec;278(52):53007-16; Clapperton JA et al. Nat. Struct. Mol. Biol., 2004 Jun;11:512-8; Glover JN, Fam. Cancer 2006; 5(1):89-93; Anantha RW et al. Elife, 2017 04;6; Findlay GM et al. Nature, 2018 10;562:217-222; Fernandes VC et al. J Biol Chem, 2019 04;294:5980-5992; Petitalot A et al. Mol Cancer Res, 2019 01;17:54-69). Multifactorial and computational likelihood models predict this variant to be deleterious (Karchin R, PLoS Comput. Biol. 2007 Feb; 3(2):e26; Iversen ES, Cancer Epidemiol. Biomarkers Prev. 2011 Jun; 20(6):1078-88; Lee JS et al. J Med Genet, 2018 12;55:794-802; Parsons MT et al. Hum Mutat, 2019 09;40:1557-1578). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 10, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1697 of the BRCA1 protein (p.Cys1697Arg). 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: 11157798, 11389159, 18465347, 36537080). This variant is also known as 5208T>C. ClinVar contains an entry for this variant (Variation ID: 55392). 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, 11389159, 14534301, 20516115, 28398198, 30209399, 30257991). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.9	D;N;.;D;.;.;N;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;.;D;.;.;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;.;.;D
Polyphen		0.92, 1.0	.;P;.;.;.;D;.;.;.;D;.
Vest4		0.94
MVP		0.99
MPC		0.60
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80356993; hg19: chr17-41215954; COSMIC: COSV99070787; COSMIC: COSV99070787;