17-43124094-C-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):c.3G>A(p.Met1?) variant causes a start lost 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1 O:1
• Conservation: PhyloP100: 3.43

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_007294.4 (BRCA1) was described as [Pathogenic] in ClinVar as 55072
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43124094-C-T is Pathogenic according to our data. Variant chr17-43124094-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43124094-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3G>A	p.Met1?	start_lost	2/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3G>A	p.Met1?	start_lost	2/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Met1? variant was identified in 3 of 59400 proband chromosomes (frequency: 0.00005) from families in a worldwide study by Rebbeck (2018). The variant was also identified in LOVD 3.0 (1x as pathogenic). Please note another variants, c.3G>T and c.3G>C at the same position with different nucleotide change and same amino acid change, p.Met1? were found in ClinVar Database and were classified as pathogenic by multiple submitters. The c.3G>A variant occurs in the first base of the translation initiation site (the methionine amino acid start site), increasing the likelihood this variant may disrupt translation or lead to an abnormal protein product. The variant was not identified in dbSNP, ClinVar, or UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 29, 2021

This variant disrupts the translation initiation codon of the BRCA1 protein and is expected to result in an absent or non-functional protein product. A functional study has reported that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been observed in at least two individuals affected with breast cancer (PMID: 9145677; Color internal data). Different variants that also disrupted the translation initiation codon, p.Met1, have also been reported in at least eight individuals affected with breast, ovarian and fallopian tube cancer (PMID: 11595708, 12827452, 16912212, 22006311, 24504028, 24884479, 25480878, 32008151, 33471991; Leiden Open Variation Database DB-ID BRCA1_002590). 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 Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 21, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Studies have shown that disruption of the initiator codon alters BRCA1 gene expression (PMID: 21922593). ClinVar contains an entry for this variant (Variation ID: 431194). A different variant (c.1A>G, c.2T>G, c.2T>C, and c.3G>T) giving rise to the same protein effect has been determined to be pathogenic (PMID: 10923033, 11595708, 11802209, 12827452, 21120943, 22006311, 24504028). This suggests that this variant is also likely to be causative of disease. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the BRCA1 mRNA. The next in-frame methionine is located at codon 18. -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

research

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Jan 31, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.90	D;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;D
MetaSVM	Uncertain	0.52	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Benign	-1.0	N;N;N;N;N;N;N;.;N;N;N;D;N;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Benign	0.48	T;D;D;T;T;.;D;.;D;.;D;.;.;.
Polyphen		0.92, 0.66, 0.99	.;P;.;.;P;.;D;.;.;.;.;.;.;.
Vest4		0.93
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);
MVP		0.89
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 21

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80357475; hg19: chr17-41276111;