17-43057117-C-T

Position:

• chr17-43057117-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5212G>A​(p.Gly1738Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1738E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:15 U:1 O:1
• Conservation: PhyloP100: 4.68

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 16 ACMG points.

• PM1: In a mutagenesis_site Abolishes interaction with BRIP1. (size 0) in uniprot entity BRCA1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43057116-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 17-43057117-C-T is Pathogenic according to our data. Variant chr17-43057117-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 55461.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43057117-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-43057117-C-T is described in Lovd as [Pathogenic]. Variant chr17-43057117-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5212G>A	p.Gly1738Arg	missense_variant	19/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5212G>A	p.Gly1738Arg	missense_variant	19/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4 Uncertain:1 Other:1

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, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	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 = 1 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 23, 2021	Variant summary: BRCA1 c.5212G>A (p.Gly1738Arg) results in a non-conservative amino acid change located in the BRCT linker domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found not found in 278112 control chromosomes (gnomAD). c.5212G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer where it co-segregated with the disease in over 8 families (e.g. Anagnostopoulos 2008, Konstantopoulou 2008, Chenevix-Trench 2006, Konstantopoulou 2014). These data indicate that the variant is very likely to be associated with disease. Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated severely diminished transcriptional activity, destabilization of the BRCT structure, reduced capacity to form foci in response to DNA damage, and increased centrosome amplification (Carvalho 2007, Lovelock 2007, Lee 2010, Thouvenot 2016, Findlay 2018). Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=8)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variation is a missense mutation, substituting Glycine with Arginine at codon 1738 of the BRCA1 protein p.(Gly1738Arg). The glycine residue is highly conserved among species and is located in a domain of the protein that is not known to be functionally important. There is a large physicochemical difference between glycine and arginine (Grantham Score 125). This variant is not present in population databases (rs80356937) and has been reported in international literature in breast and/or ovarian cancer patients and is a founder mutation in the Greek population (PMID: 17902052, PMID: 23536787, PMID: 15353005, PMID: 24010542, PMID: 17453335, PMID: 16489001). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging. In addition, experimental studies have shown that this missense variant is deleterious (PMID: 17305420, 18036263, 20516115, 17308087). A different missense substitution at this codon (p.Gly1738Glu) has been determined to be pathogenic (PMID: 18465347, PMID: 23113073, PMID: 21918854, PMID: 11157798, PMID: 10811118). This suggests that the glycine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 10, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1738 of the BRCA1 protein (p.Gly1738Arg). 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: 15353005, 16489001, 17453335, 17902052, 23536787, 24010542). It is commonly reported in individuals of Greek ancestry (PMID: 15353005, 17902052, 23536787). ClinVar contains an entry for this variant (Variation ID: 55461). 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. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17305420, 17308087, 18036263, 20516115). This variant disrupts the p.Gly1738 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10811118, 11157798, 18465347, 21918854, 23113073). 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, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 02, 2022	The BRCA1 c.5212G>A; p.Gly1738Arg variant (rs80356937) is reported in the literature in several individuals with hereditary breast and ovarian cancer syndrome and shown to co-segregate with disease in multiple families (Anagnostopoulos 2008, Heramb 2018, Jakimovska 2018, Tsaousis 2019). This variant is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 55461). Functional studies show the variant causes altered protein function (Lee 2010, Lovelock 2007). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 1738 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.762). Based on available information, this variant is considered to be pathogenic. References: Anagnostopoulos T et al. G1738R is a BRCA1 founder mutation in Greek breast/ovarian cancer patients: evaluation of its pathogenicity and inferences on its genealogical history. Breast Cancer Res Treat. 2008 Jul;110(2):377-85. PMID: 17902052. Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. PMID: 29339979. Jakimovska M et al. BRCA1 and BRCA2 germline variants in breast cancer patients from the Republic of Macedonia. Breast Cancer Res Treat. 2018 Apr;168(3):745-753. PMID: 29335924. Lee MS et al. Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Res. 2010 Jun 15;70(12):4880-90. PMID: 20516115. Lovelock PK et al. Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants? Breast Cancer Res. 2007;9(6):R82. PMID: 18036263. Tsaousis GN et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. PMID: 31159747. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 18, 2018	Not found in the total gnomAD dataset, and the data is high quality (0/282860 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Appears to be associated with disease in multiple families. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 24, 2022	The p.G1738R pathogenic mutation (also known as c.5212G>A), located in coding exon 18 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5212. The glycine at codon 1738 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21). This mutation is one of four Greek founder mutations which together account for 73% of mutations identified in BRCA1 in the Greek population (Anagnostopoulos T et al. Breast Cancer Res Treat. 2008;110(2):377-85). In two studies, this variant was identified in 0.4% to 3% of sporadic Greek breast and/or ovarian cancer families and in 3.7% to 12% of Greek carriers of a deleterious BRCA1 or BRCA2 mutation (Armaou S et al. Br J Cancer. 2009,7;101(1):32-7; Stavropoulou AV et al. PLoS One. 2013;8(3)). In addition, this alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). Multiple functional assays, including protease sensitivity, phosphopeptide binding activity, phosphopeptide binding specificity, and transcriptional assays have shown a deleterious effect (Karchin R et al. PLoS Comput. Biol. 2007;3(2):e26; Lovelock PK et al. Breast Cancer Res. 2007;9(6):R82); Carvalho MA et al. Cancer Res. 2007;15;67(4):1494-501; Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90; Thouvenot P et al. PLoS Genet. 2016 Jun 6;12(6):e1006096). In addition, one functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 Oct;562(7726):217-222). Of note, this variant may be referred to as G1738R (5331G>A) in some literature. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 23, 2023	This missense variant replaces glycine with arginine at codon 1738 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 impacts BRCA1 function in transcription activation, haploid cell proliferation, yeast colony size, centrosome amplification, and radiation-induced nuclear foci assays (PMID: 14534301, 17308087, 18036263, 20516115, 27272900, 28781887, 30209399). This variant has been reported in dozens of individuals and families affected with breast and/or ovarian cancer (PMID: 12142080, 15353005, 17902052, 19491894, 22085629, 23536787, 29310832, 30340058, 30446274, 33274848) and is known as a founder mutation in the Greek population based on haplotype analysis (PMID: 17902052, 24010542). This variant has also been identified in 39 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). . This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different nucleotide change c.5212G>C resulting in the same protein consequence (ClinVar variation ID: 865165) and other missense substitutions at the same codon (p.Gly1738Glu, p.Gly1738Val) are known to be disease-causing in ClinVar (variation ID: 55462, 845528). This indicates the important role of glycine at this codon in BRCA1 function. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Oct 25, 2021	- -

Familial cancer of breast Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	.;T;.;.;T;T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	2.0	.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.6	D;N;.;D;.;.;N;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0030	D;D;.;D;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		0.95, 1.0	.;P;.;.;.;D;.;.
Vest4		0.97
MVP		0.87
MPC		0.098
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.88
gMVP		0.85

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: rs80356937; hg19: chr17-41209134;