Submissions for variant NM_007294.4(BRCA1):c.144G>A (p.Met48Ile)

gnomAD frequency: 0.00001  dbSNP: rs587783040

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000637653	SCV000759122	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775192	SCV000909418	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-22	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 48 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported to have a neutral effect in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in two individuals in a study of breast cancer affected and unaffected controls in Africa, however, the carrier cancer history was not specified (PMID: 31871109). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000775192	SCV003879671	likely benign	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Pathway Genomics	RCV000144580	SCV000189888	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2014-07-24	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000144580	SCV001241578	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354062	SCV001548581	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Met48Ile variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, BIC, ARUP Laboratories, and Zhejiang University databases. The variant was identified in dbSNP (ID: rs587783040) as "With Uncertain significance allele ", and in ClinVar (classified as uncertain significance by Invitae, Pathway Genomics) databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Met48 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.