rs80357475

Positions:

• chr17-43124094-C-A
• chr17-43124094-C-G
• chr17-43124094-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>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:8 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 Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43124094-C-A is Pathogenic according to our data. Variant chr17-43124094-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 55072.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43124094-C-A is described in Lovd as [Pathogenic]. Variant chr17-43124094-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3G>T	p.Met1?	start_lost	2/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.3G>T	p.Met1?	start_lost	2/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459880 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726430

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: reviewed by expert panel

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, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.994371 -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change affects the initiator methionine of the BRCA1 mRNA. The next in-frame methionine is located at codon 18. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9145677, 22006311; Invitae). This variant is also known as Met1Ile. ClinVar contains an entry for this variant (Variation ID: 55072). Studies have shown that disruption of the initiator codon alters BRCA1 gene expression (PMID: 21922593). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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 the literature in multiple individuals affected by breast cancer (Rebbeck 2018, Lang 2017, Walsh 2011, Gao 2020). The variant was identified in dbSNP (ID: rs80357475), ClinVar (Pathogenic, 3 stars, reviewed by expert panel. Classified as pathogenic by ENIGMA, CIMBA, Fulgent, Ambry, Invitae, Women's College Hospital, BIC, University of Washington), LOVD 3.0 (4 entries, pathogenic), and ARUP Laboratories (Class 5-Definitely pathogenic) databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Genome Aggregation Database (March 6, 2019, v2.1.1). The p.Met1 residue is conserved in mammals and other organisms, and computational analyses (SIFT, Polyphen2, MT, FATHMM, DANN, MetaLR, Revel) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. This sequence change affects the initiator methionine of the BRCA1 mRNA. While it is expected to result in an absent or disrupted protein product, alternate in-frame methionines downstream of the initiator codon could potentially rescue the translation initiation. A saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.3G>T produced a function score of -1.9, corresponding to a functional classification of loss of function (Findlay 2018). Another experimental study found that expressing a different variant (p.Met1Arg) in yeast cells, disrupted the initiator methionine and resulted in no protein product (Millot 2011), suggesting that disruption of the initiator methionine affects translation initiation and results in loss of BRCA1 protein function.  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

Ambry Genetics

Mar 27, 2019

The p.M1? pathogenic mutation (also known as p.M1I, c.3G>T), located in coding exon 1 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3. This changes the amino acid from a methionine to an isoleucine at the initiation codon. This alteration has been reported in multiple individuals suspected of hereditary breast and/or ovarian cancer (Shih HA et al. J Clin Oncol. 2002 Feb 15;20(4):994-9; Abkevich V et al. J Med Genet. 2004 Jul;41(7):492-507; Millot GA et al. Hum Mutat. 2012 Nov;33(11):1526-37; Walsh T et al. PNAS. 2011; 108(44):18032-7). This mutation is believed to shift the initiation codon to position 18, producing a BRCA1 protein truncated by 17 amino acids (Couch FJ and Weber BL. Hum Mutat. 1996;8(1):8-18). Well established evidence from the literature on the BRCA1 RING domain indicates the crucial importance of the first 17 amino acids in maintaining the normal structure and function of the protein (Brzovic PS et al Nat Struct Biol. 2001; 8(10): 833-7; Brzovic PS et al J Biol Chem. 2001; 276(44):41399-406; Brzovic PS et al PNAS. 2003;100(10):5646-51). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature 2018 10;562(7726):217-222). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;.;.;.;T;.;T;T;.;T;T;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.77	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
Varity_R		0.91
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs80357475; hg19: chr17-41276111;