rs80357410

chr17-43124027-A-Cchr17-43124027-A-Gchr17-43124027-A-T

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>G(p.Cys24Gly) 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:2 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-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-43124027-A-C is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.70T>G	p.Cys24Gly	missense_variant	2/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.70T>G	p.Cys24Gly	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:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2020

The p.C24G pathogenic mutation (also known as c.70T>G), located in coding exon 1 of the BRCA1 gene, results from a T to G substitution at nucleotide position 70. The cysteine at codon 24 is replaced by glycine, an amino acid with highly dissimilar properties. This alteration was identified in a cohort of 313 unselected individuals with breast cancer from China (Li G et al. J. Cancer Res. Clin. Oncol., 2017 Oct;143:2011-2024). This variant is non-functional in multiple assays including BARD1 binding, E3 Ubiquitin Ligase activity and a haploid cell survival assay (Findlay GM. Nature. 2018 10;562(7726):217-222; Starita LM et al. Genetics, 2015 Jun;200:413-22). 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). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Multiple pathogenic alterations are located at this position highlighting its sensitivity to amino acid substitution (Ambry internal data). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 25, 2020

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. This variant disrupts the p.Cys24 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 25823446, 20103620, 18489799, 11320250), and experimental studies suggest this cysteine residue is critical for protein function (PMID: 11526114, 22843421, 21725363, 23161852, 25823446, 30209399). As a result, variants that disrupt this residue are likely to be causative of disease. Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. This variant has been observed in an individual affected with breast cancer (PMID: 28664449). ClinVar contains an entry for this variant (Variation ID: 649351). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with glycine at codon 24 of the BRCA1 protein (p.Cys24Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. -

Breast-ovarian cancer, familial, susceptibility to, 1 Other:1

not provided, no classification provided

in vitro

Brotman Baty Institute, University of Washington

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	28
Dann	Uncertain	0.98
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.94	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	0.97	D;D;D;D;D;D;D;D;D;D;N;N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.8	N;N;N;D;N;D;N;.;N;N;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;T;T;.;D;.;D;.;D;.;.
Polyphen		0.99, 1.0, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.96
MutPred		0.96		Loss of stability (P = 0.0491);Loss of stability (P = 0.0491);Loss of stability (P = 0.0491);Loss of stability (P = 0.0491);Loss of stability (P = 0.0491);Loss of stability (P = 0.0491);Loss of stability (P = 0.0491);Loss of stability (P = 0.0491);Loss of stability (P = 0.0491);Loss of stability (P = 0.0491);Loss of stability (P = 0.0491);Loss of stability (P = 0.0491);Loss of stability (P = 0.0491);
MVP		1.0
MPC		0.48
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.99
gMVP		0.90

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: rs80357410; hg19: chr17-41276044;