17-43115743-A-C

Position:

• chr17-43115743-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.117T>G​(p.Cys39Trp) 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 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 NM_007294.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 1.24

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 5 benign, 17 uncertain 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 chr17-43115745-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, 0.988
• PP5: Variant 17-43115743-A-C is Pathogenic according to our data. Variant chr17-43115743-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 267497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43115743-A-C is described in Lovd as [Pathogenic]. Variant chr17-43115743-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.117T>G	p.Cys39Trp	missense_variant	3/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.117T>G	p.Cys39Trp	missense_variant	3/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic: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	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2019

This sequence change replaces cysteine with tryptophan at codon 39 of the BRCA1 protein (p.Cys39Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys39 amino acid residue in BRCA1, one of eight highly-conserved Cys/His residues in the N-terminal RING domain (PMID: 22843421). Other variant(s) that disrupt this residue have been observed in individuals with BRCA1-related conditions (PMID: 21232165, 23397983, 23683081, 17262179, 15024741, 18489799), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. This variant has been reported to affect BRCA1 protein function (PMID: 25823446, 30209399). This variant has been observed in two families affected with breast and/or ovarian cancer (PMID: 22762150). It has also been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 267497). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;T;.;.;.;D;.;T;T;.;T;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;H;H;H;H;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.6	D;N;N;D;D;D;N;.;N;N;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D;.;D;.;D;.;D;.;.
Polyphen		1.0, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.89
MutPred		0.98		Gain of MoRF binding (P = 0.0727);Gain of MoRF binding (P = 0.0727);Gain of MoRF binding (P = 0.0727);Gain of MoRF binding (P = 0.0727);Gain of MoRF binding (P = 0.0727);Gain of MoRF binding (P = 0.0727);Gain of MoRF binding (P = 0.0727);Gain of MoRF binding (P = 0.0727);Gain of MoRF binding (P = 0.0727);Gain of MoRF binding (P = 0.0727);Gain of MoRF binding (P = 0.0727);Gain of MoRF binding (P = 0.0727);Gain of MoRF binding (P = 0.0727);
MVP		1.0
MPC		0.52
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.99
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886040898; hg19: chr17-41267760;