rs786203663

chr17-43049164-CCACA-TCACT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PP5_Very_Strong

The NM_007294.4(BRCA1):c.5359_5363delinsAGTGA(p.Cys1787_Gly1788delinsSerAsp) variant causes a missense change. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. C1787C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 4.31

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 10 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 17 uncertain in NM_007294.4
• PP5: Variant 17-43049164-CCACA-TCACT is Pathogenic according to our data. Variant chr17-43049164-CCACA-TCACT is described in ClinVar as [Pathogenic]. Clinvar id is 187349.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5359_5363delinsAGTGA	p.Cys1787_Gly1788delinsSerAsp	missense_variant	21/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5359_5363delinsAGTGA	p.Cys1787_Gly1788delinsSerAsp	missense_variant	21/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 30, 2016	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Mar 25, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 Pathogenic based on posterior probability = 0.999. Clinical evidence used in the multifactorial likelihood analysis is from Goldgar et al 2004 (PMID: 15290653). According to current HGVS guidelines this variant should be written as c.[5359T>A;5363G>A] (Variation ID 624568). Some pipelines may detect BRCA1 c.5359_5363delinsAGTGA as two single nucleotide variants, c.5359T>A (Variation ID 55548) and c.5363G>A (Variation ID 55551). Analysis of the c.[5359T>A;5363G>A] haplotype by a calibrated functional assay in Fernandes et al 2019 (PMID: 30765603) suggests that the protein will have abrogated function, supporting the clinical results. These clinical and functional data are only applicable when this delins event is detected, or both missense variants are observed in cis. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 24, 2023	This multinucleotide variant results in the replacement of cysteine with serine at codon 1787 and glycine with aspartic acid at codon 1788 of the BRCA1 protein. This variant is also known as a haplotype c.[5359T>A;5363G>A] and p.[Cys1787Ser;Gly1788Asp]. Computational predictions for the two constituent missense variants suggest that each missense variant may independently have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that two missense variants in cis disrupt BRCA1 function in transcription activation assay (PMID: 28781887, 30765603). This variant has been observed in several individuals and families affected with breast and/or ovarian cancer (PMID: 16030099, 18284688, 23233716, 25628955, 26543556, 28959512), and one study has reported that the variants in cis segregate with disease in families with an odds of pathogenicity of 1694:1 (PMID: 15290653). Other missense variants at codon 1788 (ClinVar variation ID: 37660, 55550, 531438) and codon 1787 (ClinVar variation ID: 662455) are considered likely disease-causing, suggesting that Glycine 1788 and Cysteine 1787 are important for the protein function. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 23, 2022	The c.5359_5363delTGTGGinsAGTGA pathogenic mutation (also known as p.C1787_G1788delinsSD) is located in coding exon 20 of the BRCA1 gene. This variant results from an in-frame deletion of TGTGG and insertion of AGTGA at nucleotide positions 5359 to 5363. This results in the deletion of cysteine and glycine residues and insertion of serine and aspartic acid at codons 1787 and 1788. This mutation has been reported as two different mutations occurring in cis in the literature and is also known as c.[5359T>A; 5363G>A] and p.[C1787S; G1788D]. This alteration occurs within the H-Bonded turn of the BRCT domain of the BRCA1 protein, a domain that is critical for cell cycle regulation and DNA repair, and has been reported in several families with breast and ovarian cancer (Goldgar DE et al. Am. J. Hum. Genet. Oct 2004;75:535–44; Dean M et al. Gigascience. 2015 Nov;4:50; Weitzel JN et al. J. Clin. Oncol. 2013 Jan;31:210-6; Torres-Meija G et al. Cancer Epidemiol. Biomarkers Prev. 2015 Mar;24:498-505; Nahleh Z et al. Am J Cancer Res. 2015 Dec;5:466-71). The p.C1787S pathogenic mutation and p.G1788D pathogenic mutation have both been shown to reduce transactivation activity in yeast and mammalian cell in vitro studies (Karchin R et al. PLoS Comput. Biol. 2007 Feb;3:e26; Carvalho MA et al. Cancer Res. 2007 Feb;67:1494-501). Other functional assays demonstrated that variants p.C1787S and p.G1788D separately had no significant impact, but that their presence in the same construct significantly impaired transactivation activity levels of the BRCA1 protein (Woods NT et al. NPJ Genom Med. 2016 Mar;1:16001; Findlay GM et al. Nature. 2018 10;562:217-222). This amino acid region is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 24, 2023	This sequence change deletes 5 nucleotides and inserts 5 different nucleotides in exon 21 of the BRCA1 mRNA (c.5359_5363delinsAGTGA). This results in the replacement of 2 adjacent amino acids at codons 1787 and 1788 with 2 different amino acids (p.Cys1787_Gly1788delinsSerAsp). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 16030099, 26543556). It is commonly reported in individuals of Hispanic or Mexican ancestry (PMID: 23233716). This variant is also known as two separate missense variants in cis (Cys1787Ser and Gly1788Asp). ClinVar contains an entry for this variant (Variation ID: 187349). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function with a positive predictive value of 95%. Experimental studies have examined each missense change independent of each other, but not in the context of occurring together in cis. Nevertheless, these studies have shown that while the p.Cys1787Ser substitution does not alter protein function (PMID: 20378548, 20516115), the p.Gly1788Asp substitution has a deleterious impact on BRCA1 protein function including altered protein folding, reduced transactivation, reduced homologous recombination activity, and a reduced DNA repair response (PMID: 17305420, 25748678, 20378548, 17308087). This variant disrupts the BRCT domain, which is important for DNA repair activity (PMID: 11573086, 14576433, 15133503, 25652403). While functional studies have not been performed to directly test the effect of this variant on BRCA1 protein function, this suggests that disruption of this region of the protein is causative of disease. This variant disrupts the p.Gly1788 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9796975, 14534301, 15689452, 16267036, 18512148, 20516115, 21614564, 26689913). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 21, 2022	Variant summary: BRCA1 c.5359_5363delinsAGTGA (p.Cys1787_Gly1788delinsSerAsp) results in an in-frame deletion-insertion in the BRCT domain of the encoded protein sequence. The variant was absent in 251442 control chromosomes. c.5359_5363delinsAGTGA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, predominantly of Hispanic origin (examples: Dean_2015, Weitzel_2013, Nahleh_2015). These data indicate that the variant is very likely to be associated with disease. A functional study (Woods_2016), assessed the two missense changes together, and observed the variant to significantly affect transcription activity. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2017

This pathogenic variant is denoted BRCA1 c.5359_5363delTGTGGinsAGTGA at the cDNA level and p.Cys1787_Gly1788delinsSerAsp (C1787_G1788delinsSD) at the protein level. The normal sequence, with the bases that are deleted and inserted in brackets, is GCTC[delTGTGG][insAGTGA]TGCT. The deletion and insertion results in the change of a Cysteine to a Serine and a Glycine to an Aspartic Acid, creating two adjacent missense changes: Cys1787Ser and Gly1788Asp. This combined variant has been observed in individuals reporting a personal or family history of breast and/or ovarian cancer and noted as a recurring variant in individuals whose ancestors originated from Mexico (Weitzel 2013, Nahleh 2014, Dean 2015). BRCA1 c.5359_5363delTGTGGinsAGTGA was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Cysteine and Serine as well as Glycine and Aspartic Acid differ in polarity, charge, size or other properties, both Cys1787Ser and Gly1788Asp are considered non-conservative amino acid substitutions. This variant occurs at a position that is conserved through mammals and is located within the BRCT 2 domain and a region known to interact with multiple other proteins (Paul 2014, UniProt). Based on available data, we consider this combined variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786203663; hg19: chr17-41201181;