Submissions for variant NM_007294.4(BRCA1):c.3G>T (p.Met1Ile)

dbSNP: rs80357475

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111552	SCV001161632	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048405	SCV000076418	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-15	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000131890	SCV000186945	pathogenic	Hereditary cancer-predisposing syndrome	2019-03-27	criteria provided, single submitter	clinical testing	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111552	SCV000325811	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763402	SCV000894128	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111552	SCV000144014	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048405	SCV000587000	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000111552	SCV001243581	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357041	SCV001552369	pathogenic	not provided		no assertion criteria provided	clinical testing	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.