17-43124027-A-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5

The NM_007294.4(BRCA1):c.70T>A(p.Cys24Ser) 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 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 15 ACMG points.

• PS1: Transcript NM_007294.4 (BRCA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 868780
• 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, 0.989
• PP5: Variant 17-43124027-A-T is Pathogenic according to our data. Variant chr17-43124027-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 638952.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, not_provided=1, Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.70T>A	p.Cys24Ser	missense_variant	2/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.70T>A	p.Cys24Ser	missense_variant	2/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2019

The p.C24S variant (also known as c.70T>A), located in coding exon 1 of the BRCA1 gene, results from a T to A substitution at nucleotide position 70. The cysteine at codon 24 is replaced by serine, an amino acid with dissimilar properties. 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). Multiple pathogenic alterations are located at this position highlighting its sensitivity to amino acid substitution (Ambry internal data). Based on the majority of available evidence to date, 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

Feb 14, 2021

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 not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 638952). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with serine at codon 24 of the BRCA1 protein (p.Cys24Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jan 11, 2020

- -

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	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D;D;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;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.94	D;D;D;D;D;D;D;D;D;D;N;N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.86	N;N;N;N;N;D;N;.;N;N;N;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;T;T;.;D;.;D;.;D;.;.
Polyphen		0.98, 1.0, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.95
MutPred		0.97		Gain of ubiquitination at K20 (P = 0.0624);Gain of ubiquitination at K20 (P = 0.0624);Gain of ubiquitination at K20 (P = 0.0624);Gain of ubiquitination at K20 (P = 0.0624);Gain of ubiquitination at K20 (P = 0.0624);Gain of ubiquitination at K20 (P = 0.0624);Gain of ubiquitination at K20 (P = 0.0624);Gain of ubiquitination at K20 (P = 0.0624);Gain of ubiquitination at K20 (P = 0.0624);Gain of ubiquitination at K20 (P = 0.0624);Gain of ubiquitination at K20 (P = 0.0624);Gain of ubiquitination at K20 (P = 0.0624);Gain of ubiquitination at K20 (P = 0.0624);
MVP		1.0
MPC		0.44
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		0.88

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;