chr17-43074331-C-T

Position:

chr17-43074331-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong

The NM_007294.4(BRCA1):c.4675G>A(p.Glu1559Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,716 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1559Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:16

Conservation

PhyloP100: 3.38

Variant links:

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]

BRCA1 links:

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ACMG classification

Classification made for transcript

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-G is described in Lovd as [Pathogenic].

PP5

Variant 17-43074331-C-T is Pathogenic according to our data. Variant chr17-43074331-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37604.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074331-C-T is described in Lovd as [Pathogenic]. Variant chr17-43074331-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-43074331-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.4675G>A	p.Glu1559Lys	missense_variant, splice_region_variant	14/23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.4675G>A	p.Glu1559Lys	missense_variant, splice_region_variant	14/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461604

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000939

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 03, 2023	Criteria applied: PS3,PS4,PM2_SUP, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	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 = 0.99607 -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Nov 25, 2004	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 14, 2024	The BRCA1 c.4675G>A (p.Glu1559Lys) variant has been reported in the published literature in in multiple individuals and families with breast and/or ovarian cancer (PMIDs: 33471991 (2021), 32341426 (2020), 31825140 (2019), 30441849 (2018), 29797126 (2018), 29752822 (2018), 29446198 (2018), 25066507 (2014), 24797986 (2014), 23239986 (2012)). Functional analysis indicates that this variant interferes with normal RNA splicing (PMIDs: 31143303 (2019) and 23239986 (2012)). The frequency of this variant in the general population, 0.000032 (1/31378 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA1 mRNA splicing. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 13, 2018	- -
Likely 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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	BRCA1: PVS1, PM2, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2024	RNA studies demonstrate a damaging effect: aberrant splicing leading to the loss of the last 11 nucleotides, resulting in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (PMID: 23239986, 31143303); Multifactorial likelihood analysis suggests this variant is pathogenic (PMID: 31131967); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4794G>A; This variant is associated with the following publications: (PMID: 31825140, 29752822, 29446198, 31131967, 30441849, 33468216, 29797126, 36922883, 31294896, 30765603, 32546644, 32341426, 9974970, 11301010, 10220405, 37937776, 28781887, 33087888, 24333842, 34981296, 36367610, 17761984, 23239986, 31143303, 25066507, 24797986) -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1559 of the BRCA1 protein (p.Glu1559Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80356988, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 17761984, 23239986, 24333842, 24797986, 25066507). It has also been observed to segregate with disease in related individuals. This variant is also known as c.4794G>A. ClinVar contains an entry for this variant (Variation ID: 37604). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30765603). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in deletion of the last 11 nucleotides of exon 14 (also known as exon 15) and introduces a premature termination codon (PMID: 23239986, 31143303; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 07, 2021	Variant summary: BRCA1 c.4675G>A (p.Glu1559Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. This sequence change occurs at the last nucleotide of exon 14. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. Consistent with these predications, a functional study report that this alteration activated a cryptic splice site resulting in the loss of the last 11 nucleotides of the exon 14 (Wappenschmidt_2012). The variant was absent in 251130 control chromosomes (gnomAD). c.4675G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. Six ClinVar submitters including an expert panel (ENIGMA) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2024

The c.4675G>A pathogenic mutation (also known as p.E1559K), located in coding exon 13 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4675. The glutamic acid at codon 1559 is replaced by lysine, an amino acid with 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 vitro transcript analyses showed that this alteration activated a cryptic splice site leading to the loss of the last 11 nucleotides of the exon and causing a premature stop codon Wappenschmidt B et al. PLoS One. 2012;7(12):e50800; Wangensteen T et al. Hered Cancer Clin Pract, 2019 May;17:14). This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Callahan MJ et al. J Clin Oncol. 2007 Sep 1;25(25):3985-90; Wappenschmidt B et al. PLoS One. 2012;7(12):e50800; Tihomirova L et al. Adv Med Sci. 2014 Mar;59(1):114-9; Conner JR et al. Gynecol Oncol. 2014 Feb;132(2):280-6; De Talhouet S et al. Sci Rep, 2020 04;10:7073). This nucleotide position is highly conserved in available vertebrate species. 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 studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;T;.;.;T;.;.;.;T;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.82

T;T;T;T;T;T;T;T;T;T

M_CAP

Pathogenic

0.85

MetaRNN

Uncertain

0.68

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.070

MutationAssessor

Benign

1.8

.;L;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

N;N;.;N;.;N;N;N;N;N

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0060

D;D;.;D;.;D;D;D;D;D

Sift4G

Benign

0.066

T;D;D;D;D;D;T;.;.;D

Polyphen

0.011, 0.76

.;B;.;.;.;.;.;.;P;.

Vest4

0.79

MVP

0.81

MPC

0.10

ClinPred

0.86

GERP RS

5.5

Varity_R

0.17

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.77

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.69

Position offset: 11

DS_DL_spliceai

0.77

Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over