17-43051098-A-C

Position:

• chr17-43051098-A-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5297T>G​(p.Ile1766Ser) 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. I1766N) 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:11 U:1 O:1
• Conservation: PhyloP100: 5.03

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 18 ACMG points.

• PM1: In a strand (size 3) in uniprot entity BRCA1_HUMAN there are 5 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 chr17-43051098-A-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 17-43051098-A-C is Pathogenic according to our data. Variant chr17-43051098-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 37656.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43051098-A-C is described in Lovd as [Pathogenic]. Variant chr17-43051098-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5297T>G	p.Ile1766Ser	missense_variant	20/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5297T>G	p.Ile1766Ser	missense_variant	20/23	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:11 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	Baylor Genetics	Aug 01, 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)	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 -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 09, 2010	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1766 of the BRCA1 protein (p.Ile1766Ser). 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: 17308087, 20737206). ClinVar contains an entry for this variant (Variation ID: 37656). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 14534301, 16528612, 17305420, 17308087, 18680205, 19493677, 20516115, 30765603). 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. -
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	Apr 17, 2019	Variant summary: BRCA1 c.5297T>G (p.Ile1766Ser) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251320 control chromosomes (gnomAD). c.5297T>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018, Caligo_2009, Judkins_2005, Easton_2007). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function from multiple studies demonstrated the variant of interest to inhibit growth suppression and affect homologous recombination and to have <10% transcriptional activity compared to the wild-type (Thouvenot_2016, Caligo_2009, Carvalho_2007). Five ClinVar submissions from clinical diagnostic laboratories and an expert panel (ENIGMA) (evaluation after 2014) cite the variant four times as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2022	Multifactorial studies suggest this variant is associated with hereditary breast and ovarian cancer (Lindor 2012); Published functional studies demonstrate a damaging effect: defective transcriptional activity, reduced cell survival, and protein instability (Glover 2006, Carvalho 2007, Lee 2010, Woods 2016, Findlay 2018); Observed in individuals with personal or family history of BRCA1-related cancers (Hartmann 2001, Carvalho 2007, Guidugli 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5416T>G; This variant is associated with the following publications: (PMID: 21990134, 17308087, 18951461, 16267036, 25782689, 20737206, 21447777, 19493677, 18680205, 15235020, 17924331, 20516115, 15172985, 27272900, 28781887, 29446198, 30765603, 16528612, 14534301, 11698567, 33087888, 17305420, 34906479, 30209399, 27535533) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 15, 2019	Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 21, 2021	This missense variant replaces isoleucine with serine at codon 1766 of the BRCA1 protein. Computational and in silico lines of evidence consistently support a deleterious effect on the function of the gene or gene product (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant affects protease sensitivity, destabilizes protein, alters phosphopeptide binding specificity, disrupts transcription activity, and is deleterious in a saturation genome editing assay (PMID: 14534301, 15172985, 16528612, 17305420, 17308087, 18680205, 19493677, 20516115, 21447777, 27272900, 30209399, 30765603, 31769492). This variant has been reported in individuals and families affected with breast cancer and ovarian cancer (PMID: 16267036, 17924331, 18680205, 20737206, 29446198, 30283497, 34072659). A probability-based multifactorial likelihood model classifies the variant as Pathogenic based on co-occurence, personal and family history, and cosegregation in five families (PMID: 17924331). 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	Apr 23, 2024	The p.I1766S pathogenic mutation (also known as c.5297T>G and 5416T>G), located in coding exon 19 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5297. The isoleucine at codon 1766 is replaced by serine, an amino acid with dissimilar properties. This variant was non-functional in multiple mammalian and yeast-based assays (Findlay GM et al. Nature. 2018 10;562:217-222; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Carvalho MA et al. Cancer Res. 2007 Feb;67(4):1494-501; Caligo MA et al. Hum. Mutat. 2009 Jan;30(1):123-33). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;T;.;.;T;T;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.1	.;M;.;.;.;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.9	D;N;.;D;.;.;N;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;.;D;.;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		0.88, 0.99	.;P;.;.;.;D;.;.
Vest4		0.95
MVP		1.0
MPC		0.53
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.87
gMVP		0.92

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: rs80357463; hg19: chr17-41203115;