17-43124095-A-G

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.2T>C(p.Met1?) variant causes a start lost 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 (★★).

• 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:5 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 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 17-43124095-A-G is Pathogenic according to our data. Variant chr17-43124095-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 54745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43124095-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2T>C	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:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3 Other:1

Pathogenic, 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	Counsyl	Aug 17, 2017	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2022

The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the BRCA1 gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat. 2018 05;39(5):593-620). This alteration is predicted to result in the loss of the first 17 amino acids of BRCA1. These RING domain residues comprise a significant portion of the N-helix of the four helix bundle that is crucial for BARD1/BRCA1 dimerization which, in turn, is responsible for their mutual stability, appropriate nuclear localization, and ubiquitin ligase activity (Brzovic PS et al. Nat. Struct. Biol. 2001 Oct;8(10): 833-7; Brzovic PS et al. J. Biol. Chem. 2001 Nov;276(44):41399-406; Brzovic PS et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May;100(10):5646-51). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature. 2018 Oct;562(7726):217-222). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 17, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that disruption of the initiator codon affects BRCA1 function (PMID: 21922593, 30209399). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 54745). Disruption of the initiator codon has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 29446198). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	24
Dann	Uncertain	0.98
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Benign	-0.22	N;N;N;N;N;N;N;.;N;N;N;D;D;.
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Uncertain	0.012	D;D;D;D;D;.;D;.;D;.;D;.;.;.
Polyphen		0.97, 0.81, 1.0	.;D;.;.;P;.;D;.;.;.;.;.;.;.
Vest4		0.95
MutPred		0.99		Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);
MVP		0.88
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.30

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: rs80357111; hg19: chr17-41276112;