17-43124027-A-G

Position:

• chr17-43124027-A-G

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.70T>C​(p.Cys24Arg) 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. C24F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1 O:1
• Conservation: PhyloP100: 4.17

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 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 chr17-43124027-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 649351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-43124027-A-G is Pathogenic according to our data. Variant chr17-43124027-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43124027-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.70T>C	p.Cys24Arg	missense_variant	2/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.70T>C	p.Cys24Arg	missense_variant	2/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2 Uncertain:1 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
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, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 08, 2021	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2016	Variant summary: The BRCA1 c.70T>C (p.Cys24Arg) variant involves the alteration of a conserved nucleotide resulting in a replacement of a conserved canonical Cysteine residue of the BRCA1 domain with an Arginine. Cysteine residues are known to be essential for Zn ion coordination and for proper folding of the RING domain of the BRCA1 protein (PMID: 11573085). Mutations of these Cysteine residues are known to be clinically relevant, and predispose individuals to cancer (BIC, HGMD). Consistently, 5/5 in silico tool predict this variant to be deleterious. Furthermore, it is absent in 120972 control chromosomes. It was reported by the BIC database in two affected members of a family further supporting its pathogenicity. Multiple independent functional studies have demonstrated that this variant results in a loss of homology directed repair activity of BRCA1 in addition to a loss of E3 ubiquitin ligase activity as well as its ability to bind to the RING domain of the BARD1 protein. A congruence of multiple functional studies further supports a disease causing impact for this variant. Two databases classify variant as Pathogenic (UMD, HGMD) while ClinVar lists this variant as Uncertain dating back to an evaluation performed in 2002 prior to the publications reporting multiple functional impacts. Considering all available lines of evidence, the variant is classified as Likely Pathogenic variant in the BRCA1 gene. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 29, 2020	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys24 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18489799, 24249303, 29176636, 25823446, 30209399). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect BRCA1 protein function (PMID: 25823446, 21725363, 24489791, 11320250, 23161852). This variant has been observed in individual(s) with increased risk of breast and/or ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 55674). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 24 of the BRCA1 protein (p.Cys24Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2024

The p.C24R pathogenic mutation (also known as c.70T>C), located in coding exon 1 of the BRCA1 gene, results from a T to C substitution at nucleotide position 70. The cysteine at codon 24 is replaced by arginine, an amino acid with highly dissimilar properties. This variant is non-functional in multiple assays including a BARD1 binding assay, a E3 Ubiquitin Ligase activity assay, a homology-directed repair assay, and a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222, Starita LM et al. Genetics, 2015 Jun;200:413-22, Towler WI et al. Hum. Mutat., 2013 Mar;34:439-45). Based on internal structural assessment, this alteration disrupts one of the Zn-binding sites of the BRCA1 RING domain (Ambry internal data; Brzovic PS et al. Nat. Struct. Biol., 2001 Oct;8:833-7). Multiple pathogenic alterations are located at this position highlighting its sensitivity to amino acid substitution (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.91	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	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.79	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	Pathogenic	0.0	D;D;D;D;D;.;D;.;D;.;D;.;.
Polyphen		0.99, 1.0, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.96
MutPred		0.96		Gain of ubiquitination at K20 (P = 0.0519);Gain of ubiquitination at K20 (P = 0.0519);Gain of ubiquitination at K20 (P = 0.0519);Gain of ubiquitination at K20 (P = 0.0519);Gain of ubiquitination at K20 (P = 0.0519);Gain of ubiquitination at K20 (P = 0.0519);Gain of ubiquitination at K20 (P = 0.0519);Gain of ubiquitination at K20 (P = 0.0519);Gain of ubiquitination at K20 (P = 0.0519);Gain of ubiquitination at K20 (P = 0.0519);Gain of ubiquitination at K20 (P = 0.0519);Gain of ubiquitination at K20 (P = 0.0519);Gain of ubiquitination at K20 (P = 0.0519);
MVP		1.0
MPC		0.57
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs80357410; hg19: chr17-41276044;