rs80357150

Positions:

• chr17-43106528-C-A
• chr17-43106528-C-G
• chr17-43106528-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.140G>T​(p.Cys47Phe) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C47Y) 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:12 U:1 O:1
• Conservation: PhyloP100: 4.08

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 4 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 chr17-43106528-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 54246.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-43106528-C-A is Pathogenic according to our data. Variant chr17-43106528-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 54247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43106528-C-A is described in Lovd as [Pathogenic]. Variant chr17-43106528-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.140G>T	p.Cys47Phe	missense_variant	4/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.140G>T	p.Cys47Phe	missense_variant	4/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Medical Genetics, University Hospital of North Norway	May 01, 2016	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centro de Genética y Biología Molecular, Universidad de San Martín de Porres	Jun 06, 2016	No present in population-based study (100 controls) -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 09, 2016	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 26, 2022	The p.C47F variant (also known as c.140G>T), located in coding exon 3 of the BRCA1 gene, results from a G to T substitution at nucleotide position 140. The cysteine at codon 47 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been identified in multiple breast and/or ovarian cancer families (Scottish/N.Irish consortium. Br. J. Cancer, 2003 Apr;88:1256-62; Bonadona V et al. Genes Chromosomes Cancer, 2005 Aug;43:404-13; Jarhelle E et al. Fam. Cancer, 2017 Jan;16:1-16; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; De Talhouet S et al. Sci Rep, 2020 04;10:7073). This variant affects an amino acid that is responsible for coordinating the binding of a zinc molecule within the BRCA1 RING finger motif and most substitutions here, including to phenylalanine, are structurally and functionally deleterious (Brzovic PS et al Nat Struct Biol. 2001; 8(10): 833-7; Millot GA et al. Hum. Mutat., 2011 Dec;32:1470-80; Thouvenot P et al. PLoS Genet., 2016 06;12:e1006096; Starita LM et al. Genetics, 2015 Jun;200:413-22; Findlay GM et al. Nature, 2018 Sep;). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 07, 2022	This missense variant replaces cysteine with phenylalanine at codon 47 in the RING and BARD1 binding 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). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399) and partially abolished BRCA1 activity in the small colony phenotype (SCP) assay in yeast (PMID: 21922593). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 12698193, 15887246, 27495310, 28944232, 34072659), and has been identified in 6 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). A different variant affecting the same codon, c.140G>A (p.Cys47Tyr), is considered to be disease-causing (ClinVar variation ID: 54246), suggesting that this position is functionally and clinically important. 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 Likely Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 22, 2023	Variant summary: BRCA1 c.140G>T (p.Cys47Phe) results in a non-conservative amino acid change located in the RING-type Zinc finger domain (IPR001841) 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 249856 control chromosomes in gnomAD. c.140G>T has been reported in multiple individuals/families affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Scottish-Northern Irish Consortium_2003, Buleje_2017, Zhu_ 2022, Solano_ 2021, Rebbeck_2018). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity based on E3 ubiquitin ligase activity and binding to the BARD1 RING domain (Starita_2015). Additionally, at least one variant at the Arg148 residue has been reported as associated with disease (p.Arg148His, common DV), suggesting that this codon is functionally important. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID:15887246, 28944232, 32341426, 22505045, 27495310, 21922593, 12698193, 34072659, 25823446, 27272900, 29446198, 34403063). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, including 2 Pathogenic and 6 likely pathogenic classifications. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	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. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 21922593, 25823446, 30209399). 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. ClinVar contains an entry for this variant (Variation ID: 54247). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12698193, 15887246, 27495310, 29339979, 29446198, 32341426; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 47 of the BRCA1 protein (p.Cys47Phe). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Feb 06, 2024

- -

Familial cancer of breast Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

-

- -

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	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;T;.;.;.;D;.;T;T;T;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.9	H;H;H;H;H;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;N;N;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.1	N;N;N;D;D;D;N;.;N;N;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;.;D;.;D;D;.
Polyphen		0.48, 1.0, 1.0	.;P;.;.;D;.;D;.;.;.;.
Vest4		0.91
MutPred		0.99		Loss of disorder (P = 0.0921);Loss of disorder (P = 0.0921);Loss of disorder (P = 0.0921);Loss of disorder (P = 0.0921);Loss of disorder (P = 0.0921);Loss of disorder (P = 0.0921);Loss of disorder (P = 0.0921);Loss of disorder (P = 0.0921);Loss of disorder (P = 0.0921);Loss of disorder (P = 0.0921);Loss of disorder (P = 0.0921);
MVP		1.0
MPC		0.14
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.99
gMVP		0.89

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: rs80357150; hg19: chr17-41258545;