rs80357498

Positions:

• chr17-43115744-C-A
• chr17-43115744-C-G
• chr17-43115744-C-T

Variant summary

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

The ENST00000357654.9(BRCA1):​c.116G>T​(p.Cys39Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C39R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 ENST00000357654.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 3.48

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 hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in ENST00000357654.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43115745-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 54152.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-43115744-C-A is Pathogenic according to our data. Variant chr17-43115744-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43115744-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.116G>T	p.Cys39Phe	missense_variant	3/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.116G>T	p.Cys39Phe	missense_variant	3/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3 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, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 20, 2010	- -
Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 25, 2021	The p.C39F variant (also known as c.116G>T), located in coding exon 2 of the BRCA1 gene, results from a G to T substitution at nucleotide position 116. The cysteine at codon 39 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This nucleotide substitution was non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222), and demonstrated impaired BARD1 binding and E3 Ubiquitin Ligase activity (Starita LM et al. Genetics, 2015 Jun;200:413-22). Additionally, codon 39 is located in a critical region of the BRCA1 protein RING domain. Multiple alterations at this codon, including p.C39R, p.C39Y, and p.C39S have been shown to alter the structure of the RING domain and negatively impact protein function and binding (Ruffner H et al. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5134-9; Brzovic PS et al. Proc Natl Acad Sci USA. 2003 May;100(10):5646-51; Ransburgh DJ et al. Cancer Res. 2010 Feb 1;70(3):988-95; Sweet K et al. Breast Cancer Res Treat. 2010 Feb;119(3):737-43). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Mar 07, 2022	This missense variant replaces cysteine with phenylalanine at codon 39 in the RING domain 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 shown that this mutant protein has decreased ubiquitin protein ligase activity and is deficient in BARD1 binding, and is predicted to be non-functional for homology-directed DNA repair (PMID: 25823446, 30219179). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals affected with breast cancer (PMID: 33278427), and has been identified in one family 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). Different variants affecting the same codon, c.115T>A (p.Cys39Ser), c.115T>C (p.Cys39Arg), c.115T>G (p.Cys39Gly), c.116G>A (p.Cys39Tyr), and c.117T>G (p.Cys39Trp) are considered to be disease-causing (ClinVar variation ID: 54151, 54152, 54153, 37392, 267497), supporting that the cysteine at this position is important for protein function. Based on the available evidence, this variant is classified as Pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 12, 2022

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 39 of the BRCA1 protein (p.Cys39Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with increased risk of breast and/or ovarian cancer (PMID: 28888541, 29446198). ClinVar contains an entry for this variant (Variation ID: 37393). 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: 30209399). This variant disrupts the p.Cys39 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9808526, 11320250, 12827452, 19543972, 21725363, 21922593, 21990134, 22843421, 23161852, 24489791). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;T;.;.;.;D;.;T;T;.;T;D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.4	H;H;H;H;H;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N;N;N;D;N;D;N;.;N;N;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D;.;D;.;D;.;D;.;.
Polyphen		1.0, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.87
MutPred		0.99		Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);
MVP		1.0
MPC		0.55
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.99
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: rs80357498; hg19: chr17-41267761;