17-43045761-A-C

Position:

• chr17-43045761-A-C

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_Strong PM2_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The c.5509T>G variant in BRCA1 is a missense variant predicted to cause substitution of Tryptophan by Glycine at amino acid 1837 (p.Trp1837Gly). 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 0.533, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies with discordant results. Exhibits protein function similar to pathogenic control variants (PMIDs: 30209399, 30765603) and between what was observed for benign and pathogenic control variants (PMID:30257991) (PS3 and BS3 not met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2004.67 (based on Co-occurrence LR=1.067; Family History LR=1878.3), above the threshold for very strong evidence towards pathogenicity (>350) (PP4_Very strong met; PMIDs: 17924331, 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, PP4_Very strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA003681/MONDO:0011450/092

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1 O:1
• Conservation: PhyloP100: 4.98

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 6 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5509T>G	p.Trp1837Gly	missense_variant	23/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5509T>G	p.Trp1837Gly	missense_variant	23/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 20, 2002	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 20, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 19, 2023	This missense variant replaces tryptophan with glycine at codon 1837 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 abolishes BRCA1 function in phosphopeptide binding, transcription activation, and in a haploid cell proliferation assay, as well as disrupts the folding of the BRCT domain (PMID: 15133503, 20378548, 20516115, 29884841, 30209399). This variant has been reported in individuals who underwent BRCA gene testing (PMID: 10923033, 16267036). Different missense substitutions at this codon have been reported as disease-causing in ClinVar (variation ID: 37679, 37680, 853483, 1065962), and p.Trp1837Arg specifically has been reported in individuals and families affected with breast cancer and reported to segregate with disease in a family (PMID: 8968102, 11802209, 27741520, 28324225). 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 Likely Pathogenic. -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

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.5509T>G variant in BRCA1 is a missense variant predicted to cause substitution of Tryptophan by Glycine at amino acid 1837 (p.Trp1837Gly). 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 0.533, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies with discordant results. Exhibits protein function similar to pathogenic control variants (PMIDs: 30209399, 30765603) and between what was observed for benign and pathogenic control variants (PMID: 30257991) (PS3 and BS3 not met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2004.67 (based on Co-occurrence LR=1.067; Family History LR=1878.3), above the threshold for very strong evidence towards pathogenicity (>350) (PP4_Very strong met; PMIDs: 17924331, 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, 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.Trp1837Gly variant was identified in the literature in at least one individual referred for BRCA1 and BRCA2 testing at Myriad Genetic Laboratories (Judkins 2005). The variant was also identified in dbSNP (ID: rs80356959) “With Likely pathogenic, Uncertain significance allele”, HGMD, the ClinVar database (submitted by Ambry Genetics with a classification of uncertain significance; submitted by Invitae with no classification provided), the BIC database (1X with unknown clinical importance), and UMD (1X as an unclassified variant). The variant is located at a BRCT fold position, within the alpha helix of the C-terminal portion of the BRCA1 protein. Several in vitro studies have shown a deleterious effect of the variant on the protein structure and function, with it having a strong destabilizing effect (Glover 2006, Lee 2010, Rowling 2010, Williams 2003), compromised transcriptional activity (Lee 2010 20516115), and reduced peptide binding activity and specificity (Glover 2006, Lee 2010, Williams 2004). The p.Trp1837 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Trp1837Gly variant may impact the protein. In addition, in silico studies using protein structure-based assessment or evolutionary conservation analysis predict the variant to have a deleterious effect (Abkevich 2004, Karchin 2007, Mirkovic 2004, Williams 2003). 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 predicted pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2023

The p.W1837G variant (also known as c.5509T>G), located in coding exon 22 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5509. The tryptophan at codon 1837 is replaced by glycine, an amino acid with highly dissimilar properties. This alteration is located in the BRCT domain of BRCA1. The tandem BRCA1 BRCT domain-phosphopeptide complex is involved in the DNA damage response in BRCA1 and alterations in this region which result in loss of phosphopeptide binding or weak binding abrogate BRCA1-BACH1 interaction and are responsible for cancer predisposition (Clapperton JA et al. Nat Struct Mol Biol. 2004 Jun;11(6):512-8). A peptide binding assay demonstrated that the p.W1837G alteration shows no detectable binding to biotinylated pSer-X-X-Phe peptides (Williams RS et al. Nat Struct Mol Biol. 2004 Jun;11(6):519-25). This alteration is structurally destabilizing and would result in a void within the BRCT domain (Williams RS et al. Nat Struct Mol Biol. 2004 Jun;11(6):519-25). A thermodynamic protein stability assay demonstrated that this alteration did not result in a stable protein but, rather, resulted in inclusion bodies, and was, in fact, classified as “very destabilizing” (Rowling PJ et al. J Biol Chem. 2010 Jun 25;285(26):20080-7). 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 Oct;562:217-222). In addition, other functional assays confirm that the alteration is destabilizing and may cause a folding defect and predict a moderate functional impact that may increase cancer risk (Glover JN et al. Fam Cancer. 2006;5(1):89-93; Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90). Another alteration at the same codon, p.W1837R, has been described in individuals with personal and/or family histories consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Montagna M et al. Cancer Res. 1996;56:5466-9; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481), and has also been predicted to be likely pathogenic and deleterious in several functional studies (Williams RS et al. J. Biol. Chem. 2003; 278:53007-16; Abkevich V et al. J. Med. Genet. 2004;41:492-507; Mirkovic N et al. Cancer Res. 2004 Jun;64:3790-7; Karchin R et al. PLoS Comput. Biol. 2007;3:e26; Lee MS et al. Cancer Res. 2010;70:4880-90; Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55; Gaiser OJ et al. Biochemistry. 2004 Dec;43:15983-95). Of note, this alteration is also designated as 5628T>G in published literature. 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp1837 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8968102, 11802209, 15689452, 27741520, 28324225). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 14534301, 15133503, 20378548, 20516115, 30209399). 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. ClinVar contains an entry for this variant (Variation ID: 55607). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 16267036). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 1837 of the BRCA1 protein (p.Trp1837Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	.;T;.;T;T;T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-11	D;N;.;.;.;.;N;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;.;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;D;.;.
Vest4		0.86
MVP		0.98
MPC		0.58
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.81
gMVP		0.80

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: rs80356959; hg19: chr17-41197778;