17-43074331-C-G

Position:

• chr17-43074331-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM5 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.4675G>C​(p.Glu1559Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1559K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 3.38

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43074331-C-T is described in Lovd as [Pathogenic].
• PP5: Variant 17-43074331-C-G is Pathogenic according to our data. Variant chr17-43074331-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43074331-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4675G>C	p.Glu1559Gln	missense_variant, splice_region_variant	14/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4675G>C	p.Glu1559Gln	missense_variant, splice_region_variant	14/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 13, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.E1580Q in BRCA1 (NM_007300.4) has been previously reported as E1559Q in patients affected with breast cancer. Functional studies demonstarted a damaging effect (Davy G et al,2018). It has been submitted to ClinVar as Pathogenic. The p.E1580Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.E1580Q variant is predicted to disrupt splicing by all splice site algorithms. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratoire de Biologie et Génétique du Cancer, Centre François Baclesse	-	- -
Pathogenic, no assertion criteria provided	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 05, 2023	The c.4738G>C variant (also known as p.Glu1580Gln) is located in coding exon 13 of the BRCA1 gene. This variant results from a G to C substitution at nucleotide position 4738. The glutamic acid at codon 1580 is replaced by glutamine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 13 which makes it likely to have some effect on normal mRNA splicing. This alteration is predicted to decrease the efficiency of the native splice donor site by the BDGP and ESEfinder in silico models. RNA analysis showed that this alteration induces expression of a transcript lacking 11 nucleotides at the end of coding exon 13 (also called exon 15 in the literature-Davy G et al. Eur. J. Hum. Genet., 2017 10;25:1147-1154). Furthermore, a close match alteration at the same nucleotide position, BRCA1 c.4675G>A has been shown in multiple studies to have the same splice defect as this alteration (Wappenschmidt B et al. PLoS ONE, 2012 Dec; Wangensteen T et al. Hered Cancer Clin Pract, 2019 May;17:14; Koczkowska M et al. Cancers (Basel), 2018 Nov;10: ). This alteration was functional in a protein assay (Woods NT et al. NPJ Genom Med, 2016 Mar;1) and is predicted to be tolerated by in silico analysis. ClinVar classifies this variant (37605) as pathogenic, rated 2 stars, with 6 submissions, 7 publications (15235020, 21394826, 23239986, 28781887, 28905878 and 2 more) and no conflicts. Therefore, this variant has been classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 24, 2021	The BRCA1 c.4675G>C; p.Glu1559Gln variant (rs80356988) is reported in the literature in an individual affected with hereditary breast and ovarian cancer (HBOC) syndrome (Davy 2017). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant occurs in the last nucleotide of exon 15, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Consistent with these predictions, mRNA studies demonstrate that the variant leads to aberrant splicing, characterized by skipping of exon 15 or use of a cryptic splice donor 11 nucleotides upstream, both of which lead to frameshifts (Davy 2017). Another variant at the same nucleotide (c.4675G>A) also has been reported in HBOC patients and leads to aberrant splicing (Wangensteen 2019, Wappenschmidt 2012). Based on available information, the c.4675G>C variant is considered to be pathogenic. References: Davy G et al. Detecting splicing patterns in genes involved in hereditary breast and ovarian cancer. Eur J Hum Genet. 2017 Oct;25(10):1147-1154. PMID: 28905878. Wangensteen T et al. Diagnostic mRNA splicing assay for variants in BRCA1 and BRCA2 identified two novel pathogenic splicing aberrations. Hered Cancer Clin Pract. 2019 May 22;17:14. PMID: 31143303. Wappenschmidt B et al. Analysis of 30 putative BRCA1 splicing mutations in hereditary breast and ovarian cancer families identifies exonic splice site mutations that escape in silico prediction. PLoS One. 2012;7(12):e50800. PMID: 23239986. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 14, 2023	The BRCA1 c.4675G>C (p.Glu1559Gln) variant disrupts a canonical splice-donor site and is predicted to interfere with normal BRCA1 mRNA splicing. This variant has been reported in the published literature in individuals and families with breast and/or ovarian cancer (PMIDs: 29446198 (2018), 28975465 (2017), 27157322 (2016)). Studies assessing BRCA1 mRNA splicing report the variant causes the skipping of exon 14 by deleting the last 11 nucleotides in the exon. This improper splicing is expected to result in frameshifts in the RNA transcripts and an absent or non-functional protein product (PMIDs: 28905878 (2017), 15235020 (2004)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 01, 2020	This missense variant replaces glutamic acid with glutamine at codon 1559 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant is located in the last nucleotide of exon 14 of the BRCA1 gene and splice site prediction tools suggest that this variant may impact RNA splicing. An RNA study has shown that this variant causes deletion of the last 11 nucleotides of exon 14 (also know as exon 15 in the literature) and skipping of exon 14 in the RNA transcripts (PMID: 28905878). Both aberrant transcripts are expected to result in an absent or non-functional protein product. This variant has been reported in an individual with personal and/or family history of breast and/or ovarian cancer (PMID: 27157322). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 31, 2024	The c.4675G>C variant (also known as p.E1559Q) is located in coding exon 13 of the BRCA1 gene. This variant results from a G to C substitution at nucleotide position 4675. The glutamic acid at codon 1559 is replaced by glutamine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 13 which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA analysis showed that this alteration induces expression of a transcript lacking 11 nucleotides at the end of coding exon 13 (also called exon 15 in the literature-Ambry internal data; Davy G et al. Eur. J. Hum. Genet., 2017 10;25:1147-1154). Furthermore, a close match alteration at the same nucleotide position, BRCA1 c.4675G>A has been shown in multiple studies to have the same splice defect as this alteration (Wappenschmidt B et al. PLoS ONE, 2012 Dec; Wangensteen T et al. Hered Cancer Clin Pract, 2019 May;17:14; Koczkowska M et al. Cancers (Basel), 2018 Nov;10: ). This alteration was functional in a protein assay (Woods NT et al. NPJ Genom Med, 2016 Mar;1) and is predicted to be tolerated by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 02, 2022

This variant disrupts the c.4675 nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 23239986, 24333842, 25066507, 31143303). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. This sequence change affects codon 1559 of the BRCA1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA1 protein. This variant also falls at the last nucleotide of exon 14, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with personal and/or family history of hereditary breast and/or ovarian cancer (PMID: 28975465, 29446198). ClinVar contains an entry for this variant (Variation ID: 37605). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 28905878). 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	Benign	0.14
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.019	T
MutationAssessor	Benign	1.8	.;L;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N;N;.;N;.;N;N;N;N;N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0080	D;D;.;D;.;D;D;D;D;D
Sift4G	Uncertain	0.048	D;D;D;D;D;D;D;.;.;D
Polyphen		0.026, 0.76	.;B;.;.;.;.;.;.;P;.
Vest4		0.43
MVP		0.82
MPC		0.082
ClinPred		0.85	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.68		Position offset: 11
DS_DL_spliceai		0.90		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs80356988; hg19: chr17-41226348;